Stereoselective synthesis of benzoquinolizidines and related homologues via intramolecular addition to dihydropyridones

Article abstract of DOI:10.1016/j.tet.2016.04.022

An efficient method for the synthesis of benzoquinolizidine and benzoindolizidine alkaloid scaffolds is described. The synthetic strategy is based on the lithium-halogen exchange-initiated intramolecular conjugate addition of aryllithiums to 2,3-dihydro-4-pyridones. A similar cyclization was also carried out under free radical conditions providing the expected cyclic compounds, although with significantly lower yields. The effects of chain length and acceptor substitution pattern on the feasibility of ring construction were studied.

Full text of DOI:10.1016/j.tet.2016.04.022

Tetrahedron 72 (2016) 3032e3039
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of benzoquinolizidines and related
homologues via intramolecular addition to dihydropyridones
ꢀ
Piotr Szczesniak, Artur Ulikowski, Olga Staszewska-Krajewska, Grzegorz Lipner,
*
Bart1omiej Furman
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of benzoquinolizidine and benzoindolizidine alkaloid scaffolds is
described. The synthetic strategy is based on the lithiumehalogen exchange-initiated intramolecular
conjugate addition of aryllithiums to 2,3-dihydro-4-pyridones. A similar cyclization was also carried out
under free radical conditions providing the expected cyclic compounds, although with significantly lower
yields. The effects of chain length and acceptor substitution pattern on the feasibility of ring construction
were studied.
Received 28 January 2016
Received in revised form 18 March 2016
Accepted 7 April 2016
Available online 14 April 2016
Keywords:
Benzoquinolizidines
Alkaloids
Ó 2016 Elsevier Ltd. All rights reserved.
Dihydropyridones
Lithiumehalogen exchange
Anionic cyclizations
Radical cyclization
1. Introduction
The utility of the presented strategy depends mainly on the
availability of suitable precursors, usually synthesized by multistep
Benzoquinolizidine alkaloids represent a small class of natural
products which have attracted considerable attention because of
their interesting biological activity. Among them, emetine, isolated
from the roots of Cephalis acuminate,1 possesses antiprotozoic
properties2 and activity in the treatment of lymphatic leukemia.3
Furthermore, it used to be applied as an emetic. Tubulosine has
been isolated from the dried fruits of Alangium lamarckii4 and the
sap of Pogonopus speciosus.5 It is remarkably active against several
cancer cell lines6 and has been studied for a variety of other bi-
ological activity, such as inhibition of protein biosynthesis7 and HIV
reverse transcriptase inhibitory activity.8 Tetrabenazine is an or-
phan drug for the symptomatic treatment of hyperkinetic move-
ment disorder9 and tetrahydroberberine has significant potential as
an antimicrobial drug (Fig. 1).10
A number of useful methods for the synthesis of these alkaloids
have been developed.11 The most commonly used are different
strategies for cyclization leading to the formation of azabicyclic
scaffolds. These synthetic methods include: asymmetric
aza-Michael additions,12 organocatalytic exo-type aza-Michael ad-
ditions,13 intramolecular domino aza-Michael addition/Darzens
reaction,14 domino Knoevenagel/hetero-DielseAlder reaction.15
syntheses. Therefore, the development of a more reliable and ex-
peditious synthetic methodology, especially a useful solution to
address the problem associated with benzoindolizidine and ben-
zoquinolizidine ring system construction, is still desirable for the
synthesis of this biologically important class of natural products.
We envisioned that the target benzoindolizidine and benzo-
quinozilidine scaffolds could be obtained via intramolecular an-
ionic or radical cyclization of 2,3-dihydro-4-pyridones bearing an
ortho-bromophenyl group in the side-chain. Corresponding
enaminones are easily prepared via one-pot Mannich-Michael
cyclocondensation reaction (formal aza-DielseAlder reaction). The
retrosynthetic plan we intended to use to achieve this goal is il-
lustrated in Scheme 1.
Cyclic enaminones, particularly 6-membered enaminones (2,3-
dihydro-4-pyridones), are extraordinarily versatile intermediates
for the synthesis of piperidine-containing molecules.16 Indeed, this
heterocycle exists in numerous drugs and drug candidates as an
indispensable binding element. Moreover, the piperidine moiety is
prevalent in various structural classes of bioactive natural prod-
ucts.17 We have previously described the synthetic utility of
enaminones in azabicycloalkane synthesis.18,19 For instance, we
described a stereoselective approach to unsaturated indolizidines
involving Lewis acid-mediated tandem Mannich/Michael reactions
and the rhodium-catalyzed intramolecular conjugate addition of
* Corresponding author. Tel.: þ48 22 3432053; fax: þ48 22 6326681; e-mail
address: furbar@icho.edu.pl (B. Furman).
http://dx.doi.org/10.1016/j.tet.2016.04.022
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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P. Szczesniak et al. / Tetrahedron 72 (2016) 3032e3039
3033
Fig. 1. Representative quinolizidine alkaloids.
Scheme 1. The cyclocondensationecyclization methodology.
vinylstannanes. Such methodology was recently used as a key step
Table 1
in the synthesis of racemic Lazubine I.20 In this article we demon-
strate the application of cyclic enaminones in the stereoselective
synthesis of benzoquinolizidines and their related homologues (5-
and 7-membered rings). Our methodology is based on the intra-
molecular cyclization reaction of 2,3-dihydro-4-pyridones bearing
an ortho-bromophenyl group in the side-chain.
The scope of dihydropyridone synthesis
2. Results and discussion
Entry
Amine
n
R
Product
Yield (%)a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1c
0
0
0
0
0
0
1
1
1
1
1
1
2
2
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
87
84
75
70
72
84
81
87
74
66
65
70
86
55
As we demonstrated previously, acyclic imines undergo the re-
action with Danishefsky’s diene21 to afford the corresponding 2,3-
4-BreC6H4
4-MeOeC6H4
2-Furyl
CO2Et
i-Pr
Ph
4-BreC6H4
4-MeOeC6H4
2-Furyl
CO2Et
i-Pr
Ph
dihydropyridin-4(1H)-ones in the presence of a catalytic amount
18e20
of Yb(OTf)3
We applied that simple protocol to the direct
synthesis of dihydropyridones 2aen (Table 1). The primary amines
1aec were synthesized from commercially available compounds
according to known procedures.22 The direct three-component,
Yb(OTf)3-catalyzed coupling reaction between aldehydes, amines
1aec and Danishefsky’s diene afforded the corresponding adducts
2aen in good yields (Table 1).
9
10
11
12
13
14
As shown in Table 1, the overall yield of the reaction showed no
dependence on the nature of starting substrates and various types
of aromatic and aliphatic aldehydes were cleanly and rapidly con-
verted to the corresponding 2-substituted 2,3-dihydropyridones.
With the desired 2,3-dihydro-4-pyridones 2aen in hand, we
initiated the study of the lithiumehalogen exchange-initiated cycli-
zation reaction. Largely through the pioneering work of Parham and
co-workers, lithiumehalogen exchange reactions in aromatic sys-
tems have been shown to be possible in the presence of a variety of
common electrophilic groups (CO2H, CO2R, CN, CONR2, CX, C]NR).23
With these indications and after a few unsuccessful attempts we
found that the mixture of t-BuLi and HMPA promoted the anionic
cyclization to give the corresponding benzoquinolizidines 3aef and
benzoindolizidines 3gel in good yields and with excellent stereo-
selectivity (Table 2). We determined that the major isomers exhibit
a trans-arrangement at H-4 and H-10b for 3aef, H-4 and H-11b for
3gel, and H-4 and H-12b for 3men. The stereochemical assign-
ment in each of the adducts 3aen was firmly established by NOE
CH2CH2eC6H5
a
All yields are isolated yields after purification by column chromatography.
experiments as well as X-ray analysis of compound 3j. In each of the
analyzed compounds, the NOE spectrum showed no correlation
between protons at C-4 and C-10b for 3aef, C-4 and C-11b for 3gel,
or C-4 and C-12b for 3men. We noted also that the nature of the R
substituent on the enaminones doesn’t significantly affect the
overall yield and diastereoselectivity of the cyclization reaction. The
anionic cyclization also proved effective in the synthesis of 7-
membered analogues of benzoquinolizidines 3men. In this case,
the intramolecular addition of the aryllithium compound to
enaminones 2men proceeded in low yield, but nonetheless with
good stereoselectivity. We noted that in this case the aryllithium
compound is substantially protonated by the solvent molecules.
The results of the investigation on the anionic cyclization are
summarized in Table 2.

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P. Szczesniak et al. / Tetrahedron 72 (2016) 3032e3039
3034
Table 2
The scope of anionic cyclization
Entry
Substrate
n
R
Product
Yield (%)a
trans/cisb
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
0
0
0
0
0
0
1
1
1
1
1
1
2
2
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
72
34
69
63
38
63
71
25
74
61
32
68
20
19
trans
trans
trans
trans
99.5/0.5
99.5/0.5
trans
trans
trans
trans
99.5/0.5
trans
99.5/0.5
99.5/0.5
4-BreC6H4
4-OMe-C6H4
2-Furyl
CO2Et
i-Pr
Ph
4-BreC6H4
4-MeOeC6H4
2-Furyl
CO2Et
i-Pr
Ph
9
10
11
12
13
14
CH2CH2eC6H5
a
All yields are isolated yields after purification by column chromatography.
Determined by HPLC.
b
Next, we investigated the radical cyclization reaction of a variety
exhibiting the trans arrangement of protons, which was confirmed
by X-ray analysis.26 This rule applies to both the anionic and the
radical cyclization (Scheme 2).
of substituted 2,3-dihydro-4-pyridones 2. Recently, Ishibashi has
reported a simple access to oxindoles via the intramolecular cycli-
zation reaction of in situ generated aryl radicals to enaminones.24
Working from these results, we found that a mixture of Bu3SnH
and a catalytic amount of AIBN promoted the radical cyclization to
give the corresponding benzoquinolizidines and benzoindolizidines
in moderate yields and with high diastereoselectivity (Table 3). The
radical cyclization needed a longer reaction time and higher tem-
perature. However, the stereochemical assignment of radical cycli-
zation products was the same as observed for the anionic process.
The stereochemical outcome of these cyclizations is rationalized
in Scheme 2. Similar stereochemical preferences in Michael addi-
tions have been reported previously.25 We postulate that in the
transition state the nitrogen lone pair occupies an axial position
while the R group prefers the equatorial position. The cyclization
proceeds preferably anti to the R group, providing the adduct
3. Conclusion
In summary, a novel method for the stereoselective construction
of benzoindolizidine and benzoquinolizidine scaffolds has been
described. The structure and relative stereochemistry of the cycli-
zation products was confirmed by NMR and X-ray analysis. The
generality of this method was further tested with different ring
sizes, where dihydropyridones with a bromoaryl function located
in the side-chain underwent cyclization to give 6,7,6-fused ring
systems.
4. Experimental section
4.1. General
Table 3
The scope of radical cyclization
Column chromatography was performed on Merck silica gel,
grade 60 (230e400 mesh). TLC plates were visualized with UV and/
or staining with phosphomolybdic acid. 1H and 13C NMR spectra
were recorded on Bruker AM500 (500 MHz) and Varian (400 MHz)
spectrometers and the chemical shifts are reported in parts per
million with TMS as an internal standard (
d¼0 ppm). Signal multi-
plicities are abbreviated as follows: sesinglet, dedoublet, tetriplet,
qequartet, memultiplet. Infrared (IR) spectra were recorded using
Perkin Elmer FTIR-1600 infrared spectrophotometer. High-
resolution mass spectra were recorded using a Mariner PerSeptive
Biosystems mass spectrometer with time-of-flight (TOF) detector.
Unless stated otherwise, all reagents and solvents were purchased
from commercial sources and used without additional purification.
Entry
Substrate
n
R
Product
Yield (%)a
trans/cisb
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
0
0
0
0
0
0
1
1
1
1
1
1
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
53
34
42
53
38
32
75
20
34
34
25
42
trans
trans
trans
trans
99.5/0.5
99.5/0.5
trans
trans
trans
4-BreC6H4
4-OMe-C6H4
2-Furyl
CO2Et
i-Pr
Ph
4-BreC6H4
4-MeOeC6H4
2-Furyl
CO2Et
4.2. General procedure for enaminone 2aem synthesis via the
Lewis acid-catalyzed one-pot aza-DielseAlder reaction of
Danishefsky’s diene with imines generated in situ
9
10
11
12
2j
2k
2l
3j
3k
3l
trans
99.5/0.5
trans
i-Pr
To a solution of amine 1aec (0.5 mmol) in CH2Cl2 and molecular
ꢁ
a
sieves 4 A (50 mg) the correspondingaldehyde (0.5mmol) was added
All yields are isolated yields after purification by column chromatography.
Determined by HPLC.
b
dropwise. The flask was shielded from light with aluminum foil and

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P. Szczesniak et al. / Tetrahedron 72 (2016) 3032e3039
3035
Scheme 2. Stereochemical model of the cyclization and the crystal structure of 3j.
the reaction mixture was stirred over 8 h. The solution was filtered
through a pad of Celite and evaporated under reduced pressure. The
obtained crude imine was dissolved in dry MeCN (4 ml) without
purification and cooled to 0 ꢀC. Yb(OTf)3 (31 mg, 0.05 mmol,10 mol %)
yield 162 mg (75%); Rf 0.33 (50% acetone in hexanes); chromatog-
raphy (40% acetone in hexanes); 1H NMR (500 MHz, CDCl3)
d
7.23e7.18 (m, 3H), 7.02 (s, 1H), 6.89e6.85 (m, 2H), 6.60 (s, 1H),
5.06 (d, J¼7.7 Hz, 1H), 4.49 (m, 1H), 4.30e4.23 (m, 2H), 3.88 (s, 3H),
and Danishefsky’s diene (117 ml, 0.6 mmol, 1.2 equiv) were added
3.81 (s, 3H), 3.80 (s, 3H), 2.88 (dd, J¼16.4, 7.2 Hz, 1H), 2.65 (dd,
under argon. The reaction mixture was warmed to rt and stirred over
6 h (TLC monitoring). The reaction was quenched by saturated
aqueous NaHCO3 (5 ml). After phaseseparation, the organiclayerwas
washed three times with CH2Cl2 (10 ml), dried over Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure to give
a residue, which was purified by silica gel column chromatography to
give the corresponding enaminones (2aem).
J¼16.4, 7.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 190.3, 159.6, 153.7,
149.5, 148.7, 130.6, 128.2, 126.7, 116.0, 114.4, 114.3, 112.7, 98.4, 60.5,
56.9, 56.2, 56.1, 55.3, 43.7; HRMS (ESI-TOF) m/z calcd for
C
21H22NO479Br [Mþ] 431.0732 found 431.0751; IR (film, CH2Cl2)
nmax: 1639, 1591, 1510, 1379, 1259, 1165, 1030, 771 cmꢁ1
.
4.2.4. 1-(2-Bromo-4,5-dimethoxybenzyl)-2-(furan-2-yl)-2,3-
dihydropyridin-4(1H)-one (2d). Colorless oil; isolated yield 137 mg
(70%); Rf 0.36 (50% acetone in hexanes); chromatography (40% ac-
4.2.1. 1-(2-Bromo-4,5-dimethoxybenzyl)-2-phenyl-2,3-
dihydropyridin-4(1H)-one (2a). Colorless solid; mp 47e48 ꢀC; iso-
lated yield 175 mg (87%); Rf 0.35 (50% acetone in hexanes); chro-
matography (40% acetone in hexanes); 1H NMR (500 MHz, CDCl3)
etone in hexanes); 1H NMR (500 MHz, CDCl3)
d 7.40 (m, 1H), 7.07 (s,
1H), 7.02 (d, J¼7.7 Hz, 1H) 6.8 (s, 1H), 6.3 (m, 1H), 6.29 (m, 1H), 5.03
(dd, J¼7.7, 0.7 Hz,1H), 4.64 (dd, J¼7.0, 4.6 Hz,1H), 4.53 (d, J¼14.9 Hz,
1H), 4.36 (d, J¼14.9 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.88 (dd,
J¼16.4, 7.0 Hz, 1H), 2.72 (ddd, J¼16.4, 4.6, 0.7 Hz, 1H); 13C NMR
d
7.37e7.30 (m, 3H), 7.29e7.26 (m, 3H), 7.02 (s,1H), 6.60 (s,1H), 5.07
(d, J¼7.7 Hz, 1H), 4.55 (t, J¼7.0 Hz, 1H), 4.35e4.29 (m, 2H), 3.68 (s,
3H), 3.81 (s, 3H), 2.93 (dd, J¼16.5, 7.4 Hz, 1H), 2.66 (dd, J¼16.5,
(125 MHz, CDCl3)
d 190.1, 152.2, 151.3, 149.7, 148.7, 142.6, 126.9,
6.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 189.9, 153.9, 149.6, 148.7,
116.2, 114.5, 112.9, 110.4, 108.6, 98.4, 57.6, 56.3, 56.2, 54.0, 39.8;
HRMS (ESI-TOF) m/z calcd for C18H18NO479Br [Mþ] 391.0419 found
391.0431; IR (film, CH2Cl2) nmax: 1640, 1587, 1506, 1439, 1377, 1262,
138.6, 129.1, 128.3, 126.9, 116.0, 114.5, 112.8, 98.5, 60.9, 57.2, 56.2,
56.1, 43.4; HRMS (ESI-TOF) m/z calcd for C20H20O3N79Br [Mþ]
401.0632 found 401.0645; IR (film, CH2Cl2) nmax: 1638, 1592, 1507,
1207, 1166, 1029, 741 cmꢁ1
.
1439, 1262, 1030 cmꢁ1
.
4.2.5. Ethyl 1-(2-bromo-4,5-dimethoxybenzyl)-4-oxo-1,2,3,4-
tetrahydropyridine-2-carboxylate (2e). Colorless oil; isolated yield
163 mg (82%); Rf 0.27 (60% acetone in hexanes); chromatography
4.2.2. 1-(2-Bromo-4,5-dimethoxybenzyl)-2-(4-bromophenyl)-2,3-
dihydropyridin-4(1H)-one (2b). Colorless solid; mp 107e108 ꢀC;
isolated yield 202 mg (84%); Rf 0.38 (50% acetone in hexanes);
chromatography (40% acetone in hexanes); 1H NMR (500 MHz,
(50% acetone in hexanes); 1H NMR (500 MHz, CDCl3)
d 7.14 (dd,
J¼7.7, 1.2 Hz, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 5.02 (d, J¼7.7 Hz, 1H),
4.53e4.45 (m, 2H), 4.23 (q, J¼7.2 Hz, 2H), 4.09 (ddd, J¼6.2, 3.9,
1.1 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 2.83e2.80 (m, 2H), 1.28 (t,
CDCl3)
d
7.48e7.47 (m, 2H), 7.26 (d, J¼7.7 Hz, 1H), 7.16e7.14 (m, 2H),
7.02 (s, 1H), 6.60 (s, 1H), 5.07 (d, J¼7.7 Hz, 1H), 4.49 (t, J¼7.0 Hz, 1H),
4.34e4.29 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 2.93 (dd, J¼16.4, 7.5 Hz,
1H), 2.59 (dd, J¼16.4, 6.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 188.7, 169.9,153.2,149.9,
148.8, 126.5, 116.1, 114.9, 113.3, 99.5, 62.1, 58.8, 58.7, 56.3, 56.2, 38.0,
14.1; HRMS (ESI-TOF) m/z calcd for C17H20NO579Br [Mþ] 397.0525
found 397.0542; IR (film, CH2Cl2) nmax: 1734, 1642, 1590, 1507, 1378,
d
189.5, 153.6, 149.7, 148.7, 137.6, 132.2, 128.6, 126.2, 122.2, 116.1,
114.5, 112.7, 98.7, 60.2, 57.3, 56.3, 56.2, 43.24; HRMS (ESI-TOF) m/z
calcd for C20H19O3N79Br2 [Mþ] 478.9732 found 478.9718; IR (film,
CH2Cl2) nmax: 1639, 1588, 1571, 1507, 1379, 1262, 1221, 1205,
1166 cmꢁ1. (2b*): isolated yield 51%; HPLC: ChiralpakÒ OD-H, 100%
i-PrOH, flow 0.25 ml/min, UV 325 nm, Rt 49.8 min(minor),
60.9 min(major).
1262, 1166, 1027, 801 cmꢁ1
.
4.2.6. 1-(2-Bromo-4,5-dimethoxybenzyl)-2-isopropyl-2,3-
dihydropyridin-4(1H)-one (2f). Colorless oil; isolated yield 136 mg
(74%); Rf 0.35 (50% acetone in hexanes); chromatography (40% ac-
etone in hexanes); 1H NMR (500 MHz, CDCl3)
d 7.08e7.05 (m, 2H),
4.2.3. 1-(2-Bromo-4,5-dimethoxybenzyl)-2-(4-methoxyphenyl)-2,3-
dihydropyridin-4(1H)-one (2c). Yellow solid; mp 92e94 ꢀC; isolated
6.79 (s, 1H), 4.92 (dd, J¼7.4, 0.7 Hz,1H), 4.56, (d, J¼15.3 Hz,1H), 4.38
(d, J¼15.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.26 (m, 1H), 2.69e2.64

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P. Szczesniak et al. / Tetrahedron 72 (2016) 3032e3039
3036
(m, 1H), 2.42 (dd, J¼16.7, 2.4 Hz, 1H), 2.29 (m, 1H), 0.98 (m, 6H); 13
C
134mg(65%);Rf 0.36(50%acetoneinhexanes);chromatography(40%
acetone in hexanes); 1H NMR (400 MHz, CDCl3)
7.03 (s, 1H), 6.98 (d,
NMR (125 MHz, CDCl3)
d
190.9, 153.0, 149.6, 148.9, 127.6, 116.0,
d
113.8, 111.8, 97.5, 61.8, 58.1, 56.3, 56.2, 36.5, 29.2, 19.7, 18.0; HRMS
(ESI-TOF) m/z calcd for C17H22NO379Br [Mþ] 367.0783 found
367.0801; IR (film, CH2Cl2) nmax 1636, 1588, 1507, 1261, 1207, 1164,
J¼7.5 Hz,1H), 6.70 (s,1H), 4.96 (d, J¼7.5 Hz,1H), 4.21 (q, J¼7.2 Hz, 2H),
4.09e4.05 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.59 (dd, J¼14.3, 7.0 Hz,
1H), 3.46 (dd, J¼14.3, 6.9 Hz, 1H), 3.00e2.96 (m, 2H), 2.81e2.80 (m,
1030 cmꢁ1
.
2H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 188.5, 170.0,
153.6,148.7, 148.6, 128.7, 115.7, 114.3,113.3, 99.0, 62.1, 59.6, 56.2, 55.4,
38.0, 36.0, 29.2, 14.1; HRMS (ESI-TOF) m/z calcd for C18H22NO579Br
[Mþ] 411.0681 found411.0697; IR (film, CH2Cl2) nmax 1735, 1637, 1589,
4.2.7. 1-(2-Bromo-4,5-dimethoxyphenethyl)-2-phenyl-2,3-
dihydropyridin-4(1H)-one (2g). Colorless oil; isolated yield 169 mg
(81%); Rf 0.29 (50% acetone in hexanes); chromatography (40% ac-
1510, 1463, 1384, 1258, 1218, 1188, 1166, 1027, 791 cmꢁ1
.
etone in hexanes); 1H NMR (500 MHz, CDCl3)
d 7.38e7.28 (m, 5H),
7.06 (d, J¼7.7 Hz, 1H), 6.97 (s, 1H), 6.48 (s, 1H), 5.0 (d, J¼7.7 Hz, 1H),
4.62 (dd, J¼8.7, 7.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.34e3.25 (m,
2H), 2.89e2.76 (m, 2H), 2.79e2.74 (m, 2H); 13C NMR (125 MHz,
4.2.12. 1-(2-Bromo-4,5-dimethoxyphenethyl)-2-isopropyl-2,3-
dihydropyridin-4(1H)-one (2l). Colorless oil; isolated yield 134 mg
(70%); Rf 0.28 (50% acetone in hexanes); chromatography (40% ac-
CDCl3)
d
190.1, 153.8, 148.6, 148.5, 138.6, 129.0, 128.9, 128.3, 127.1,
etone in hexanes); 1H NMR (200 MHz, CDCl3)
d 7.02 (s, 1H), 6.89 (d,
115.6, 114.1, 113.3, 98.7, 61.6, 56.14, 56.08, 53.2, 43.8, 35.5; HRMS
(ESI-TOF) m/z calcd for C21H22O3NO79Br [Mþ] 415.0783 found
415.0796; IR (film, CH2Cl2) nmax 1635, 1591, 1578, 1509, 1439, 1383,
J¼6.5 Hz, 1H), 6.67 (s, 1H), 4.83, (d, J¼6.5 Hz, 1H), 3.86 (s, 3H), 3.82
(s, 3H), 3.51e3.44 (m, 2H), 3.29e3.18 (m, 1H), 2.94e2.90 (m, 2H),
2.60 (dd, J¼16.6, 7.3 Hz, 1H), 2.37 (dd, J¼16.6, 3.7 Hz, 1H), 2.30e2.10
1257, 1218, 1165, 1033, 792, 701 cmꢁ1
.
(m, 1H), 0.96e0.89 (m, 6H); 13C NMR (50 MHz, CDCl3)
d 190.7, 152.6,
148.7, 148.5, 128.7, 115.8, 114.1, 113.7, 97.3, 62.3, 56.1, 54.6, 52.8, 37.0,
36.9, 29.0, 19.7, 18.1; HRMS (ESI-TOF) m/z calcd for C18H24NO379Br
[Mþ] 381.0936 found 381.0955; IR (film, CH2Cl2) nmax 1632, 1585,
4.2.8. 1-(2-Bromo-4,5-dimethoxyphenethyl)-2-(4-bromophenyl)-
2,3-dihydropyridin-4(1H)-one (2h). Colorless oil; isolated yield
215 mg (87%); Rf 0.27 (50% acetone in hexanes); chromatography
1509, 1464, 1385, 1259, 1220, 1165, 1032, 790, 731 cmꢁ1
.
(40% acetone in hexanes); 1H NMR (500 MHz, CDCl3)
d 7.51e7.48
(m, 2H), 7.19e7.17 (m, 2H), 7.07 (d, J¼7.7 Hz,1H), 6.98 (s,1H), 6.51 (s,
1H), 5.03 (d, J¼7.7 Hz, 1H), 4.65e4.45 (m, 1H), 3.86 (s, 3H), 3.81 (s,
3H), 3.34e3.30 (m, 2H), 2.95e2.90 (m, 2H), 2.83 (dd, J¼15.6, 7.6 Hz,
4.2.13. 1-(3-(2-Bromo-4,5-dimethoxyphenyl)propyl)-2-phenyl-2,3-
dihydropyridin-4(1H)-one (2m). Colorless oil; isolated yield 151 mg
(70%); Rf 0.42 (20% acetone in hexanes); chromatography (30% ac-
1H), 2.65 (dd, J¼15.6, 7.6 Hz,1H); 13C NMR (125 MHz, CDCl3)
d
189.7,
etone in hexanes); 1H NMR (400 MHz, CDCl3)
d 7.37e7.28 (m, 5H),
153.7, 148.7, 148.6, 137.7, 132.2, 128.7, 128.6, 122.3, 115.7, 114.2, 113.2,
7.19 (d, J¼7.6 Hz, 1H), 6.98 (s, 1H), 6.59 (s, 1H), 5.08 (d, J¼7.6 Hz, 1H),
4.66 (dd, J¼7.8, 7.3 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.19e3.13 (m,
2H), 2.90 (dd, J¼16.4, 7.5 Hz, 1H), 2.71(dd, J¼16.4, 7.5 Hz, 1H),
2.67e2.61 (m, 1H), 2.58e2.49 (m, 1H), 1.87e1.77 (m, 2H); 13C NMR
98.9, 61.0, 56.2, 56.1, 53.3, 43.5, 35.6; HRMS (ESI-TOF) m/z calcd for
C
21H21NO379Br2 [Mþ] 492.9888 found 492.9879; IR (film, CH2Cl2)
nmax 1635, 1586, 1509, 1439, 1383, 1258, 1219, 1165, 1035, 1010,
791 cmꢁ1. (2h*): isolated yield 48%; HPLC: ChiralpakÒ OD-H, 100% i-
PrOH, flow 0.25 ml/min, UV 325 nm, Rt 53.6 min (minor), 65.9 min
(major).
(100 MHz, CDCl3)
d 190.1, 154.2, 148.5, 148.1, 138.5, 131.8, 129.0,
128.3, 127.0, 115.7, 114.0, 112.7, 98.4, 61.0, 56.2, 56.1, 53.1 43.6, 33.0,
29.1; HRMS (ESI-TOF) m/z calcd for C22H24NO379Br [Mþ] 429.0940
found 429.0957; IR (film, CH2Cl2) nmax 1636, 1592, 1578, 1508, 1442,
4.2.9. 1-(2-Bromo-4,5-dimethoxyphenethyl)-2-(4-methoxyphenyl)-
2,3-dihydropyridin-4(1H)-one (2i). Colorless oil; isolated yield
165 mg (74%); Rf 0.31 (50% acetone in hexanes); chromatography
1383, 1257, 1216, 1164, 1030, 701 cmꢁ1
.
4.2.14. 1-(3-(2-Bromo-4,5-dimethoxyphenyl)propyl)-2-phenethyl-
2,3-dihydropyridin-4(1H)-one (2n). Colorless oil; isolated yield
167 mg (73%); Rf 0.38 (20% acetone in hexanes); chromatography
(40% acetone in hexanes); 1H NMR (500 MHz, CDCl3)
d 7.31e7.27
(m, 2H), 7.08 (d, J¼7.6 Hz, 1H), 7.02 (s, 1H), 6.96e6.91 (m, 2H), 6.51
(s, 1H), 5.04 (d, J¼7.6 Hz, 1H), 4.62 (dd, J¼9.0, 7.0 Hz, 1H), 3.89 (s,
3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.35e3.28 (m, 2H), 2.91e2.83 (m, 2H),
(30% acetone in hexanes); 1H NMR (400 MHz, CDCl3)
d 7.31e7.25
(m, 3H), 7.23e7.13 (m, 2H), 7.0 (s, 1H), 6.94 (d, J¼7.5 Hz, 1H), 6.65
(s, 1H), 4.94 (d, J¼7.5 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.51e3.46
(m, 1H), 3.30e3.14 (m, 2H), 2.82 (dd, J¼16.5, 6.8 Hz, 1H), 2.78e2.58
(m, 3H), 2.57e2.42 (m, 2H), 2.21e2.08 (m, 1H), 1.95e1.80 (m, 3H);
2.77e2.74 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 190.4, 159.6, 153.8,
148.52, 148.46, 130.7, 129.0, 128.4, 115.7, 114.3, 114.1, 113.4, 98.6, 61.1,
56.15, 56.10, 55.3, 53.0, 44.0, 35.5; HRMS (ESI-TOF) m/z calcd for
C
22H24NO479Br [Mþ] 445.0889 found 445.0881.; IR (film, CH2Cl2)
13C NMR (100 MHz, CDCl3)
d 190.2, 152.4, 148.5, 148.2, 140.7, 131.8,
nmax 1635, 1586, 1509, 1439, 1383, 1258, 1219, 1165, 1035, 1010,
128.6, 128.2, 126.2, 115.7, 113.9, 112.8, 97.0, 56.2, 56.1, 55.6, 53.4,
791 cmꢁ1
.
39.1, 32.9, 31.6, 30.0, 29.8; HRMS (ESI-TOF) m/z calcd for
C
24H28NO379Br [Mþ] 457.1253 found 457.1264; IR (film, CH2Cl2)
4.2.10. 1-(2-Bromo-4,5-dimethoxyphenethyl)-2-(furan-2-yl)-2,3-
dihydropyridin-4(1H)-one (2j). Colorless oil; isolated yield 134 mg
(66%); Rf 0.34 (50% acetone in hexanes); chromatography (40%
nmax 1633, 1584, 1508, 1454, 1441, 1383, 1256, 1216, 1164, 1030, 752,
700 cmꢁ1
.
acetone in hexanes); 1H NMR (500 MHz, CDCl3)
d
7.41 (dd, J¼1.8,
4.3. General procedure for anionic cyclization
0.8 Hz, 1H), 7.01 (s, 1H), 6.86 (d, J¼7.5 Hz, 1H) 6.6 (s, 1H), 6.35 (dd,
J¼3.3, 1.8 Hz, 1H), 6.32 (dd, J¼3.3, 0.8 Hz, 1H), 4.98 (d, J¼7.5 Hz, 1H),
4.69e4.64 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.48e3.43 (m, 2H),
2.96e2.90 (m, 2H), 2.80e2.77 (m, 2H); 13C NMR (125 MHz, CDCl3)
To a solution of enaminone 2aem (0.2 mmol) in dry THF (5 ml)
HMPA (87 ul, 0.5 mmol, 2.5 equiv) and t-BuLi 1.7 M (in pentane)
(295 ul, 0.5 mmol, 2.5 equiv) were added under argon at ꢁ78 ꢀC.
The reaction mixture was stirred at ꢁ78 ꢀC for 2 h (TLC monitoring).
After the substrate was consumed, the reaction mixture was
warmed to ꢁ10 ꢀC and quenched with H2O (10 ml). After phase
separation, the organic layer was washed three times with CH2Cl2
(10 ml), dried over Na2SO4 and filtered. The filtrate was concen-
trated under reduced pressure to give a residue, which was purified
by silica gel column chromatography to give the corresponding
adducts (3aem).
d
190.0, 152.7, 151.1, 148.7, 148.5, 142.7, 128.8, 115.7, 114.2, 113.5,
110.4, 108.7, 98.1, 56.2, 56.1, 54.6, 53.9, 39.9, 36.1; HRMS (ESI-TOF)
m/z calcd for C19H20NO479Br [Mþ] 405.0555 found 405.0545; IR
(film, CH2Cl2) nmax 1635, 1583, 1509, 1439, 1383, 1258, 1219, 1165,
1033, 771 cmꢁ1
.
4.2.11. Ethyl 1-(2-bromo-4,5-dimethoxyphenethyl)-4-oxo-1,2,3,4-
tetrahydropyridine-2-carboxylate (2k). Colorless oil; isolated yield

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P. Szczesniak et al. / Tetrahedron 72 (2016) 3032e3039
3037
4.4. General procedure for radical cyclization
110.3, 108.3, 107.5, 106.1, 60.4, 56.1, 56.0, 55.6, 54.0, 46.3, 44.1;
HRMS (ESI-TOF) m/z calcd for C18H19NO4 [Mþ] 313.1312 found
313.1325; IR (film, CH2Cl2) nmax 1712, 1505, 1465, 1366, 1320, 1217,
To a solution of enaminone 2ael (0.1 mmol) in benzene (15 ml)
tributyltin hydride (Bu3SnH) (32 ul, 0.12 mmol 1.2 equiv) and AIBN
(3.2 mg, 0.02 mmol, 20 mol %) were added under argon. The re-
action mixture was stirred at 80 ꢀC for 16 h (TLC monitoring). After
the substrate was consumed, the reaction mixture was evaporated
under reduced pressure. The crude product was diluted with ace-
tonitrile (10 ml), and washed three times with hexanes. The ace-
tonitrile phase was concentrated under reduced pressure to give
a residue, which was purified by silica gel column chromatography
to give the corresponding adducts (3ael).
1188, 1112, 1018, 747 cmꢁ1
.
4.4.5. (4R*,10bR*)-Ethyl 8,9-dimethoxy-2-oxo-1,2,3,4,6,10b-hexahy-
dropyrido[2,1-a]isoindole-4-carboxylate (3e). Yellow oil; isolated
yield 24 mg (38%) for anionic cyclization, 12 mg (38%) for radical
cyclization; Rf 0.29 (50% AcOEt in hexanes); chromatography (40%
AcOEt in hexanes); 1H NMR (500 MHz, C6D6)
d: 6.50 (s, 1H), 6.34 (s,
1H), 4.64 (dd, J¼11.4, 2.6 Hz, 1H), 4.27 (dd, J¼11.5, 2.5 Hz, 1H),
3.94e3.88 (m, 3H), 3.74 (dd, J¼6.8, 3.6 Hz, 1H), 3.43 (s, 3H), 3.41 (s,
3H), 2.70 (dd, J¼14.2, 3.1 Hz, 1H), 2.63 (dd, J¼15.2, 3.5 Hz, 1H); 2.39
(dd, J¼15.2, 6.8 Hz, 1H); 2.21 (dd, J¼14.2, 11.5 Hz, 1H), 0.58 (t,
4.4.1. (4R
*
,10bR )-8,9-Dimethoxy-4-phenyl-1,3,4,10b-tetrahydropyr-
*
ido[2,1-a]isoindol-2(6H)-one (3a). Yellow solid; mp 101e103 ꢀC;
isolated yield 47 mg (72%) for anionic cyclization, 17 mg (53%) for
radical cyclization; Rf 0.24 (50% AcOEt in hexanes); chromatogra-
J¼7.2 Hz, 3H); 13C NMR (125 MHz, C6D6)
d: 204.2, 170.9, 150.2, 150.1,
134.9, 131.0, 107.4, 106.0, 61.0, 60.6, 58.8, 55.9, 55.7, 46.3, 45.0, 42.0,
14.3; HRMS (ESI-TOF) m/z calcd for C17H21NO5 [Mþ] 319.142 found
319.141; IR (film, CH2Cl2) nmax 1726, 1689, 1499, 1292, 1198, 1122,
phy (40% AcOEt in hexanes); 1H NMR (500 MHz, C6D6)
d: 7.30e7.14
(m, 5H), 6.39 (s, 1H), 6.34 (s, 1H), 4.62e4.56 (m, 1H), 4.00 (d,
J¼12.7 Hz, 1H), 3.87 (dd, J¼11.2, 3.5 Hz, 1H), 3.58e3.53 (m, 1H), 3.41
(m, 6H), 2.58 (dd, J¼16.7, 11.2 Hz, 1H), 2.50e2.44 (m, 2H), 2.34 (dd,
1027 cmꢁ1
.
4.4.6. (4R*,10bR*)-4-Isopropyl-8,9-dimethoxy-1,3,4,10b-tetrahy-
dropyrido[2,1-a]isoindol-2(6H)-one (3f). Yellow oil; isolated yield
36 mg (63%) for anionic cyclization, 9 mg (32%) for radical cycli-
zation; Rf 0.33 (50% AcOEt in hexanes); chromatography (40% AcOEt
J¼16,1, 12.4 Hz, 1H); 13C NMR (125 MHz, C6D6)
d 207.0, 150.3, 150.0,
143.4, 134.2, 130.7, 128.9, 128.8, 107.1, 106.4, 96.4, 62.8, 61.7, 58.7,
56.0, 55.9, 48.1, 44.8; HRMS (ESI-TOF) m/z calcd for C20H21NO3 [Mþ]
323.1523 found 323.1511; IR (film, CH2Cl2) nmax 1718, 1507, 1454,
in hexanes); 1H NMR (500 MHz, C6D6)
d: 6.54 (s, 1H), 6.38 (s, 1H),
1356, 1224, 1190, 1111, 756, 702 cmꢁ1
.
4.46 (dt, J¼11.9, 3.4 Hz, 1H), 4.14 (d, J¼12.1 Hz, 1H), 3.72 (ddd,
J¼12.1, 3.4, 0.7 Hz, 1H), 3.49 (s, 3H), 3.47 (s, 3H), 2.71e2.68 (m, 1H),
2.35 (dd, J¼15.5, 3.5 Hz, 1H), 2.28 (d, J¼2.4 Hz, 2H), 2.13 (dd, J¼15.5,
11.9 Hz, 1H), 1.74 (m, 1H), 0.92 (d, J¼6.8 Hz, 3H), 0.86 (d, J¼6.8 Hz,
4.4.2. (4R ,10bR*)-4-(4-Bromophenyl)-8,9-dimethoxy-1,3,4,10b-tet-
*
rahydropyrido[2,1-a]isoindol-2(6H)-one (3b). Yellow solid; mp
136e137 ꢀC; isolated yield 27 mg (34%) for anionic cyclization,
14 mg (34%) for radical cyclization; Rf 0.28 (50% AcOEt in hexanes);
chromatography (40% AcOEt in hexanes); 1H NMR (500 MHz, C6D6)
3H); 13C NMR (125 MHz, C6D6)
d: 208.0, 150.1, 149.9, 135.5, 130.6,
107.3, 106.4, 64.3, 62.2, 58.2, 56.1, 56.0, 45.2, 39.1, 30.8, 19.4, 17.2;
HRMS (ESI-TOF) m/z calcd for C17H23NO3 [Mþ] 289.168 found
289.168; IR (film, CH2Cl2) nmax 1716, 1506, 1351, 1322, 1222, 1190,
d
7.34 (d, J¼8.4 Hz, 2H), 7.16e7.13 (s, 2H), 6.94 (d, J¼8.3 Hz, 2H), 6.42
(s, 1H), 6.34 (s, 1H), 4.44 (t, J¼5.0 Hz, 1H), 3.92 (m, 1H), 3.47e3.43
1113, 1002 cmꢁ1
.
(m, 1H), 3.45 (s, 3H), 3.41 (s, 3H), 2.48e2.38 (m, 2H), 2.35e2.25 (m,
2H); 13C NMR (125 MHz, C6D6)
d
206.6, 150.4, 150.1, 142.4, 134.0,
4.4.7. (4R*,11bR*)-9,10-Dimethoxy-4-phenyl-3,4,6,7-tetrahydro-1H-
pyrido[2,1-a]isoquinolin-2(11bH)-one (3g). Colorless solid; mp
139e141 ꢀC; isolated yield 48 mg (71%) for anionic cyclization,
25 mg (75%) for radical cyclization; Rf 0.36 (50% AcOEt in hexanes);
chromatography (40% AcOEt in hexanes); 1H NMR (500 MHz,
132.0, 130.5, 129.0, 121.4, 107.0, 106.4, 62.2, 61.7, 58.6, 56.0, 55.9,
47.8, 44.7; HRMS (ESI-TOF) m/z calcd for C20H20NO379Br [Mþ]
401.0634 found 401.0623; IR (film, CH2Cl2) nmax 1719, 1508, 1325,
1224, 1191, 1112, 1009, 839 cmꢁ1
.
CDCl3) d: 7.35e7.29 (m, 5H), 6.60 (s, 1H), 6.47 (s, 1H), 4.54 (t,
4.4.3. (4R
*
,10bR*)-8,9-Dimethoxy-4-(4-methoxyphenyl)-1,3,4,10b-
J¼5.1 Hz, 1H), 4.07 (dd, J¼8.9, 4.9 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H),
tetrahydropyrido[2,1-a]isoindol-2(6H)-one (3c). Orange solid; mp
122e124 ꢀC; isolated yield 49 mg (69%) for anionic cyclization,
15 mg (42%) for radical cyclization; Rf 0.32 (50% AcOEt in hexanes);
chromatography (40% AcOEt in hexanes); 1H NMR (500 MHz, C6D6)
3.28e3.24 (m, 1H), 2.95e2.80 (m, 5H), 2.78 (ddd, J¼15.0, 4.1, 1.1 Hz,
1H), 2.71 (dd, J¼14.8, 9.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d:
208.0,152.3,147.4,139.5,128.7,128.3,128.1,127.5,126.0,111.5,108.9,
96.9 63.9, 55.9, 54.2, 46.9, 46.5, 43.6, 29.7 28.7; HRMS (ESI-TOF) m/z
calcd for C21H23NO3 [Mþ] 337.1678 found 337.1695; IR (film,
CH2Cl2) nmax 1706,1610, 1517, 1451, 1357,1256,1232,1129, 1021, 769,
d
: 7.34 (d, J¼8.6 Hz, 2H), 6.92 (d, J¼8.6 Hz, 2H), 6.73e6.66 (m, 2H),
4.48 (t, J¼5.0 Hz, 1H), 3.88e3.80 (m, 1H), 3.49e3.45 (m, 1H), 3.45 (s,
3H), 3.42e3.39 (m, 6H), 3.32 (dd, J¼12.3, 3.2 Hz, 1H), 2.99 (d,
J¼13.6 Hz, 1H), 2.75e2.58 (m, 4H); 13C NMR (125 MHz, C6D6)
702 cmꢁ1
.
d
205.1, 154.7, 152.7, 147.7, 132.1, 131.9, 129.8, 128.8, 114.7, 108.4,
4.4.8. (4R*,11bR*)-4-(4-Bromophenyl)-9,10-dimethoxy-3,4,6,7-
tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (3h). Colorless
solid; mp 128e129 ꢀC; isolated yield 21 mg (25%) for anionic cy-
clization, 8 mg (20%) for radical cyclization; Rf 0.31 (50% AcOEt in
hexanes); chromatography (40% AcOEt in hexanes); 1H NMR
105.1, 67.6, 65.2, 59.7, 55.1, 52.3, 52.7, 48.0, 42.7; HRMS (ESI-TOF) m/
z calcd for C21H23NO4 [Mþ] 353.1632 found 353.1621; IR (film,
CH2Cl2) nmax 1715, 1511, 1464, 1306, 1247, 1224, 1175, 1112, 1033,
839 cmꢁ1
.
(200 MHz, CDCl3)
d (ppm): 7.48e7.44 (m, 2H), 7.28e7.24 (m, 2H),
4.4.4. (4R*,10bR*)-4-(Furan-2-yl)-8,9-dimethoxy-1,3,4,10b-tetrahy-
dropyrido[2,1-a]isoindol-2(6H)-one (3d). Dark brown oil; isolated
yield 39 mg (63%) for anionic cyclization, 17 mg (53%) for radical
cyclization; Rf 0.35 (50% AcOEt in hexanes); chromatography (40%
6.60 (s, 1H), 6.45 (s, 1H), 4.14 (t, J¼5.0 Hz, 1H), 4.08 (dd, J¼14.6,
7.1 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.30e3.24 (m, 1H), 2.89e2.84
(m, 4H), 2.75e2.61 (m, 3H); 13C NMR (50 MHz, CDCl3)
d: 206.1,
150.4,149.6,142.6,135.5, 133.2,128.7,128.2,122.3,110.2,108.9, 63.9,
AcOEt in hexanes); 1H NMR (500 MHz, C6D6)
d: 7.06 (dd, J¼1.8,
58.9, 55.9, 52.2, 46.9, 45.1, 41.5, 30.2; HRMS (ESI-TOF) m/z calcd for
0.8 Hz, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 6.12 (m, 1H), 6.05 (dd, J¼3.2,
1.8 Hz,1H), 4.23e4.18 (m, 2H), 4.09 (dd, J¼11.8, 2.2 Hz,1H), 3.89 (dd,
J¼11.8, 2.2 Hz, 1H), 3.43 (s, 3H), 3.42 (s, 3H), 2.68e2.63 (m, 2H), 2.58
(dd, J¼15.3, 6.2 Hz, 1H), 2.29 (dd, J¼14.4, 11.6 Hz, 1H); 13C NMR
C
21H2279BrNO3 [Mþ] 415,0785 found 415,0742; IR (film, CH2Cl2)
nmax 1716, 1510, 1337, 1256, 1232, 1189, 1131, 851 cmꢁ1
.
4.4.9. (4R*,11bR*)-9,10-Dimethoxy-4-(4-methoxyphenyl)-3,4,6,7-
tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (3i). Colorless
(125 MHz, C6D6)
d
: 205.5, 154.6, 150.0, 149.9, 142.2, 134.8, 131.3,

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P. Szczesniak et al. / Tetrahedron 72 (2016) 3032e3039
3038
solid; mp 123e125 ꢀC; isolated yield 54 mg (74%) for anionic cy-
clization, 12 mg (34%) for radical cyclization; Rf 0.28 (50% AcOEt in
hexanes); chromatography (40% AcOEt in hexanes); 1H NMR
351.1834 found 351.1824; IR (film, CH2Cl2) nmax 1707, 1454,
705 cmꢁ1
.
(200 MHz, CDCl3)
d
: 7.30e7.25 (m, 2H), 6.89e6.85 (m, 2H), 6.61 (s,
4.4.14. (4S*,12bR*)-10,11-Dimethoxy-4-phenethyl-1,3,4,7,8,12b-hex-
ahydrobenzo[c]pyrido[1,2-a]azepin-2(6H)-one (3n). Yellow oil; iso-
lated yield 14 mg (19%) for anionic cyclization; Rf 0.31 (50% AcOEt in
hexanes); chromatography (40% AcOEt in hexanes); 1H NMR
1H), 6.48 (s, 1H), 4.44 (t, J¼5.0 Hz, 1H), 4.08 (dd, J¼9.5, 4.9 Hz, 1H),
3.85e3.79 (m, 10H), 3.29e3.23 (m, 1H), 2.95e2.70 (m, 6H); 13C
NMR (50 MHz, CDCl3) d: 209.1, 158.8, 147.6, 147.4, 131.6, 129.2,
128.8, 126.0, 113.6, 111.5, 108.9, 63.4, 55.8, 55.2, 54.0, 46.9, 46.5,
43.7, 29.7, 28.7; HRMS (ESI-TOF) m/z calcd for C22H25NO4 [Mþ]
367.1784 found 367.17957; IR (film, CH2Cl2) nmax 1707, 1463,
(400MHz, CDCl3)d:7.28e7.10(m, 5H), 6.65(s,1H), 6.61(s,1H), 3.86(s,
3H), 3.80 (s, 3H), 3.41e3.37 (m,1H), 3.15e2.57 (m, 6H), 2.47e2.37 (m,
2H), 2.33e2.20 (m, 2H), 1.74e1.50 (m, 1H), 1.27e1.22 (m, 4H); 13C
830 cmꢁ1
.
NMR (100 MHz, CDCl3) d: 210.8,147.2,146.5,141.8,132.4,128.5,128.3,
128.2, 126.0, 113.4, 112.0, 60.8, 56.0, 55.9, 53.0, 47.6, 46.6, 33.9, 31.8,
4.4.10. (4R*,11bR*)-4-(Furan-2-yl)-9,10-dimethoxy-3,4,6,7-
tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (3j). Colorless
solid; mp 109e111 ꢀC; isolated yield 40 mg (61%) for anionic cy-
clization, 11 mg (34%) for radical cyclization; Rf 0.33 (50% AcOEt in
hexanes); chromatography (40% AcOEt in hexanes); 1H NMR
31.5, 29.7, 25.8; HRMS (ESI-TOF) m/z calcd for C24H29NO3 [Mþ]
379.2147 found 379.2161; IR (film, CH2Cl2) nmax 1705,1458, 706 cmꢁ1
.
Acknowledgements
(500 MHz, C6D6)
d
: 7.04 (dd, J¼1.9, 0.8 Hz, 1H), 6.40 (s, 1H), 6.19 (s,
We wish to thank the State Committee for Scientific Research
(Grant NN 204 2380 34) for the support of this work.
1H), 6.16 (m, 1H), 6.03 (dd, J¼3.3, 1.8 Hz, 1H), 4.10 (t, J¼4.6 Hz, 1H),
3.87 (dd, J¼11.2, 3.3 Hz, 1H), 3.43 (s, 3H), 3.31 (s, 3H), 2.97e2.85 (m,
3H), 2.71e2.65 (m, 1H), 2.59e2.57 (m, 2H), 2.52e2.46 (m, 1H), 2.33
References and notes
(dd, J¼14.5, 11.4 Hz, 1H); 13C NMR (125 MHz, C6D6)
d: 205.8, 153.6,
148.8, 148.8, 142.2, 129.8, 126.4, 112.7, 110.2, 109.7, 109.5, 59.2, 55.7,
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C
19H22NO4 [MþHþ] 328.1543 found 328.1557; IR (film, CH2Cl2) nmax
1713, 1465, 743 cmꢁ1
.
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4.4.11. (4R*,11bR*)-Ethyl-9,10-dimethoxy-2-oxo-2,3,4,6,7,11b-hex-
ahydro-1H-pyrido[2,1-a]isoquinoline-4-carboxylate (3k). Yellow oil;
isolated yield 21 mg (32%) for anionic cyclization, 8 mg (25%) for
radical cyclization; Rf 0.35 (50% AcOEt in hexanes); chromatogra-
phy (40% AcOEt in hexanes); 1H NMR (200 MHz, CDCl3)
d: 6.6 (s,
1H), 6.53 (s, 1H), 4.18e4.14 (m, 3H), 4.01 (dd, J¼6.3, 1.7 Hz, 1H), 3.85
(s, 3H), 3.82 (s, 3H), 3.17e2.62 (m, 7H), 2.39 (dd, J¼14.9,11.2 Hz,1H),
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d: 201.5, 163.5,
148.6,144.8,124.3,123.1,106.1,106.0, 61.7, 60.6, 59.2, 57.0, 53.9, 51.7,
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333.1576 found 333.1589; IR (film, CH2Cl2) nmax 1724, 1465,
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4.4.12. (4R*,11bR*)-4-Isopropyl-9,10-dimethoxy-3,4,6,7-tetrahydro-
1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (3l). Yellow oil; isolated
yield 41 mg (68%) for anionic cyclization, 13 mg (42%) for radical
cyclization; Rf 0.34 (50% AcOEt in hexanes); chromatography (40%
ꢀ
3752; (e) Lin, S.; Deiana, L.; Tseggai, A.; Cordova, A. Eur. J. Org. Chem. 2012, 398.
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d: 6.62 (s, 1H), 6.50
(s, 1H), 4.19 (dd, J¼11.5, 3.3 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H),
3.35e3.29 (m, 1H), 3.13e3.05 (m, 1H), 2.86e2.79 (m, 2H),
2.75e2.60 (m, 3H), 2.54e2.48 (m, 1H), 2.44 (dd, J¼14.0, 3.4 Hz,
1H), 1.72 (ddd, J¼16.7, 12.9, 6.5 Hz, 1H), 0.97 (d, J¼6.9 Hz, 3H), 0.95
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Fustero, S.; Sanchez-Rosello, M.; del Pozo, C. Pure Appl. Chem. 2010, 82, 669; (h)
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ꢀ
ꢀ
ꢀ
(d, J¼6.9 Hz, 3H); NMR (50 MHz, CDCl3)
d
: 210.4, 155.2, 150.9,
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28.6, 18.3, 16.9; HRMS (ESI-TOF) m/z calcd for C18H25NO3 [Mþ]
303.1834 found 303.1823; IR (film, CH2Cl2) nmax 1706, 1465,
ꢀ
ꢀ
ꢀ
ꢀ
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ꢀ
ꢀ
732 cmꢁ1
.
ꢀ
ꢀ
4.4.13. (4R*,12bR*)-10,11-Dimethoxy-4-phenyl-1,3,4,7,8,12b-hexahy-
drobenzo[c]pyrido[1,2-a]azepin-2(6H)-one (3m). Yellow oil; isolated
yield 14 mg (20%) for anionic cyclization; Rf 0.27 (50% AcOEt in
hexanes); chromatography (40% AcOEt in hexanes); 1H NMR
ꢀ
ꢀ
ꢀ
Moscardo, J.; Sanchez-Rosello, M.; Rodríguez, E.; Barrio, P. Org. Lett. 2010, 12,
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(500 MHz, CDCl3) d: 7.34e7.22 (m, 5H), 6.76 (s,1H), 6.72 (s,1H), 4.86
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(dd, J¼5.5, 2.4 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.65 (dd, J¼9.5,
4.0 Hz, 1H), 3.16e2.94 (m, 5H), 2.74 (dd, J¼14.6, 5.8 Hz, 1H), 2.61
(dd, J¼16.1, 9.5 Hz, 1H), 2.51 (dd, J¼16.1, 4.0 Hz, 1H), 1.51e1.23 (m,
€
Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (e) Grossmann, A.; Enders,
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d: 210.8, 147.2, 146.3, 141.3, 135.2,
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132.2, 128.6, 128.2, 127.7, 113.4, 112.4, 59.7, 57.9, 56.0, 55.8, 54.6,
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2095.
26. Crystallographic data for the structure 3j in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
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