Radical intramolecular arylation of pyridinium salts: A straightforward entry to 7-hydroxypyrido[2,1-a]isoquinolinylium salts

Article abstract of DOI:10.1002/ejoc.201001071

The synthesis of 7-hydroxypyrido[2,1-a]isoquinolinylium salts can be achieved in moderate yields by intramolecular radical arylation of pyridinium salts obtained from substituted pyridines and o-bromophenacyl bromides. The synthesis of 7-hydroxypyrido[2,1

Full text of DOI:10.1002/ejoc.201001071

FULL PAPER
DOI: 10.1002/ejoc.201001071
Radical Intramolecular Arylation of Pyridinium Salts: A Straightforward
Entry to 7-Hydroxypyrido[2,1-a]isoquinolinylium Salts
Rafael R. Castillo,[a] Carolina Burgos,*[a] Juan J. Vaquero,[a] and Julio Alvarez-Builla*[a]
Keywords: Radical reactions / Nitrogen heterocycles / Intramolecular arylation
The synthesis of 7-hydroxypyrido[2,1-a]isoquinolinylium
radical arylation of pyridinium salts obtained from substi-
salts can be achieved in moderate yields by intramolecular
tuted pyridines and o-bromophenacyl bromides.
knowledge, only a few examples of radical arylations of
pyridinium derivatives have been published. Thus, after the
pioneering work by Park[7] concerning the study of tran-
sient species from the laser photolysis of N-(2Ј-halobenzyl)-
pyridinium bromides, Jones and co-workers[8] reported a 5-
exo/endo-trig cyclization in which a pyridinium radical was
added to another arene nucleus, with subsequent rearo-
matisation. In this context, as part of our work on free-
radical heteroarylations using TTMSS/AIBN,[9] our group
has published a new synthesis of pyridopyrazole derivatives
through an aryl radical addition to a π-deficient pyridinium
Introduction
On studying the intramolecular radical arylation of pyr-
idinium salts, we discovered that there is no precedent for
the preparation of 7-hydroxypyrido[2,1-a]isoquinolinylium
salts (e.g. 1a, Scheme 1), and only few papers concerning
the synthesis and reactivity of 3-hydroxyquinolizinium salts
2 have been published.[1] Other related derivatives are
known,[2] and in the case of fused compounds (e.g. 3,
Scheme 1), some examples have been described by Matsuda
et al.[3] as intermediates of heteroannulenes. However, sev-
eral papers have been published on the synthesis and reac-
tivity of pyrido[2,1-a]isoquinolinylium derivatives, which
are, in their hydrogenated forms, the basis of different natu-
ral alkaloids. Thus, this heterocyclic skeleton is an interest-
ing motif for medicinal chemistry.[4]
fragment linked to
a
π-excessive 2-azinyliminopyr-
idine moiety.[10] Despite the fact that radical homolytic aro-
matic substitution has been studied by various research
groups,[11] we wish to report here the preparation of a series
of compounds containing a hydroxyquinolizinium fragment
fused to a benzene ring. The route starts from the appropri-
ate pyridinium salt, and proceeds through an aryl radical
cyclisation onto a pyridinium fragment.
Results and Discussion
Our initial studies in the area started from the pyrid-
inium salts 6 (Scheme 2), obtained from substituted pyr-
idines 5a–k by reaction with different o-bromophenacyl
bromides 4a–c. Compounds 6 are the starting materials for
the radical cyclization process. Bearing in mind previous
results reported by Harrowven and co-workers[12] and by
ourselves,[9,10] the aryl radical 7, derived from 6, can cyclize
at the ortho position through a 6-endo/exo-trig process to
supply the pyridinium salt 8, which is in tautomeric equilib-
rium with 7-hydroxypyrido[2,1-a]isoquinolinylium salts 1.
As indicated in Scheme 2 and Table 1, 7-hydroxypyrido[2,1-
a]isoquinolinylium salt 1a was obtained by the slow drop-
wise addition (using a syringe pump) of a solution of
2 equiv. of both TTMSS and AIBN in m-xylene to a solu-
tion, at reflux temperature, of pyridinium salt 6a in dry ace-
tonitrile (entry 1). The reaction did not go to completion
when only 1 equiv. of both TTMSS and AIBN was em-
Scheme 1. Some examples of hydroxyquinolizinium salts.
The generation and subsequent reaction of aryl radicals,
derived from aryl halides using tris(trimethylsilyl)silane and
azobis(isobutyronitrile) (TTMSS/AIBN), in the construc-
tion of nitrogen heterocycles is well documented, and sev-
eral syntheses based on aryl radical cyclizations have been
reported.[5] The first example of an intramolecular radical
addition to quaternized pyridinium salts was described by
Murphy and coworkers[6] for the preparation of five-, six-
and seven-membered rings. However, to the best of our
[a] Departamento de Química Orgánica, Universidad de Alcalá,
28871 Alcalá de Henares, Spain
Fax: +34-91-885-4686
E-mail: julio.alvarez@uah.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001071.
Eur. J. Org. Chem. 2011, 619–628
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
619

R. R. Castillo, C. Burgos, J. J. Vaquero, J. Alvarez-Builla
FULL PAPER
ployed, a finding consistent with previous experience.[6,10] rivative (1x, X = C, entry 3, Table 2) and the worst for the
Furthermore, attempts to cyclize 6 in the presence of base phthalazinium derivative (1z, X = N, entry 5, Table 2).
did not increase the yield of the process. A wide range of
Although all described compounds are obtained with
starting materials was tested in this reaction. For example, modest yields, these are common in this kind of chemistry.
the presence of electron-withdrawing substituents in the Moreover, a carbonyl substituent in the bromoaryl moiety
pyridinium moiety led to a decrease in the yield of the cycli- could additionally disturb the radical process, because this
zation product (R5 = CF3, CN, entries 6 and 7, respec- group could work as an electron-withdrawing substituent,
tively).
furnishing a decrease in the yield of the cyclization process,
with debrominated compound formation being favoured.
As far as the radical pathway is concerned, although sev-
eral reaction mechanisms could explain this transformation,
the simplest pathway involves a 6-exo/endo-trig cyclization
as described in Scheme 3. This pathway is consistent with
the production of cyclic compounds 1. Taking into con-
sideration the results reported by Minisci et al.,[15] Russell
et al.[16] and those from our own work,[10] additional experi-
ments were undertaken in the presence of potassium car-
bonate as a base. In these cases, however, reaction yields
were not improved. This lack of improvement shows the
preference of intermediate 9 to act as a proton acceptor
(Scheme 3) or, alternatively, suggests that, under these cir-
cumstances, an H-abstraction mechanism may be in opera-
tion.[11e,17]
Scheme 2. Preparation of the starting material 6 and the 7-hy-
droxypyrido[2,1-a]isoquinolinylium salts 1 by a radical cyclization
process.
In contrast, the best results – albeit with only moderate
increases – were obtained when electron-donating substitu-
ents were located in both the 3- and 5-positions of the pyr-
idinium ring (R4 and R6, respectively, entries 10 and 11,
Table 1), an observation consistent with previous re-
ports.[9,13] The effect of substituents in the bromoaryl moi-
ety was also examined (entries 12–21). The presence of elec-
tron-withdrawing substituents such as fluorine led to slight
decreases in the yield of the cyclization process (entries 12–
Scheme 3. Suggested pathway for the preparation of hydroxypyr-
ido[2,1-a]isoquinolinylium salts 1 by a radical cyclization process.
Taking into consideration the recent work from Yuan
15). Once again, the best results were obtained with elec- and co-workers[18] concerning Friedel–Crafts-type reactions
tron-donating substituents (entries 16–21, Table 1). On the of heterocyclic imines with aromatic substrates, and with
basis of these results, the introduction of electron-donating the aim to rule out an eventual oxidation mechanism, after
substituents in both aromatic rings seems to be the most Friedel–Crafts substitution for these processes, additional
efficient way to improve the yield of the salts 1. Addition- experiments were carried out. Thus, the debrominated start-
ally, salts 6 with a methoxy group in the 4-position of the ing material, phenacylpyridinium bromide (6aa),[19] was
pyridinium ring (i.e. 6h and 6s, R5 = OMe, entries 8 and prepared and tested under standard cyclization conditions
19, respectively, Table 1), after radical cyclization and work- by using TTMSS and AIBN. As expected, the reaction did
up, produced only demethylated compounds (i.e. 1h and 1s, not provide the cyclic derivative 1a, and only starting mate-
R5 = OH, entries 8 and 19, respectively, Table 1). A similar rial was detected by HPLC-MS.
phenomenon has been described,[14] and is thought to be
the result of hydrolysis of the 4-methoxy group on the pyr- obtained from commercially available azines 5 by alkylation
Starting azinium salts 6a–z (Table 1 and Table 2) were
idinium ring in the presence of base.
with the corresponding o-bromophenacyl bromides 4 in dry
The method was extended to other azinium salts, and acetone, in a sealed tube at 50 °C.[20] The o-bromophenacyl
representative results are shown in Table 2. In general, bromides 4 were obtained from commercial sources or from
yields were comparable to those obtained with pyridinium previously reported[21] o-bromoacetophenones. Bromina-
salts, with the best yield for the 3-methylisoquinolinium de- tion occurred in the α-position to the keto group in the
620
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 619–628

Radical Intramolecular Arylation of Pyridinium Salts
Table 1. Preparation of starting materials 6a–u and synthesis of hydroxypyrido[2,1-a]isoquinolinylium salts 1a–u by intramolecular radical
arylation.
Entry
4
5
R1
R2
R3
R4
R5
R6
6
6
R1
R2
R3
R4
R5
R6
1
1
Yield
Yield
[%][a,b]
[%][a,b]
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
H
H
H
H
H
Me
H
Me
H
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
Me
H
H
H
H
H
H
H
tBu
Ph
CF3
CN
OMe
H
H
H
H
H
H
H
H
Ph
CF3
OMe
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
Me
H
H
H
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
73
76
82
89
79
81
93
77
90
77
85
83
72
84
89
95
82
86
91
79
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
H
H
H
H
H
Me
H
Me
H
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
Me
H
H
H
H
H
H
H
tBu
Ph
CF3
CN
OH
H
H
H
H
H
H
H
H
Ph
CF3
OH
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
Me
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
42
39
46
39
33
36
12
35
36
44
50
39
29
26
35
44
44
47
43
42
47
9
10
11
12
13
14
15
16
17
18
19
20
21
5j
6j
6k
6l
1j
1k
1l
5k
5a
5b
5c
5j
F
F
F
6m
6n
6o
6p
6q
6r
6s
6t
F
F
F
1m
1n
1o
1p
1q
1r
1s
1t
5a OMe OMe
5e OMe OMe
5f
5h OMe OMe
5j OMe OMe
OMe OMe
OMe OMe
OMe OMe
OMe OMe
OMe OMe
OMe OMe
Me
Me
Me
Me
Me
Me
Me
Me
5k OMe OMe Me
H
6u
OMe OMe Me
H
1u
[a] Yields for isolated products. [b] For detailed conditions see following section.
presence of B(OMe)3 and Br2 according to a literature
Experimental Section
method.[22]
General Remarks: All chemicals and solvents were purchased from
commercial sources. Infrared spectra were recorded with a Perkin–
Elmer FTIR 1725X spectrophotometer. H and 13C NMR spectra
1
Conclusions
were recorded with either Varian Gemini (200 MHz), Unity or
Mercury (300 MHz) spectrometers; chemical shifts are given in
ppm (δ) downfield from TMS. Melting points were obtained with
a Stuart Scientific SMP3 apparatus in open capillary tubes, and are
uncorrected. Elemental analyses were carried out with a Heraeus
Rapid CHN analyser, and are within Ϯ0.4% of the theoretical val-
ues for all compounds described. Mass spectra were collected with
an Agilent 1100 HPLC/MS. High resolution mass spectra were ob-
tained with an Agilent 6210 Time-of-Flight LC/MS.
In conclusion, the synthesis of 7-hydroxypyrido[2,1-a]-
isoquinolinylium salts 1 and related compounds by intra-
molecular radical arylation of suitable substrates is de-
scribed. The methodology seems to be efficient and flexible
enough to prepare this kind of derivatives, although with
modest yields. In agreement with previously reported obser-
vations, the presence of electron-donating substituents on
both aromatic rings seems to facilitate the arylation process.
The method has been tentatively extended to other azinium
derivatives, and gave comparable results. Although several
reaction mechanisms can explain the observed transforma-
tions, reasonable pathways leading to the formation of the
observed products are suggested.
Compounds 4a,[22] 4b,[23] 6a,[24] 6aa,[19] and 6b[25] have been de-
scribed previously.
2-Bromo-1-(2-bromo-4,5-dimethoxyphenyl)-ethanone (4c): To a solu-
tion of the corresponding o-bromoacetophenone[21] (2.59 g,
10 mmol) in methanol (15 mL) was added trimethyl borate (1.56 g,
15 mmol). The mixture was stirred at room temperature for 45 min,
Eur. J. Org. Chem. 2011, 619–628
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
621

R. R. Castillo, C. Burgos, J. J. Vaquero, J. Alvarez-Builla
FULL PAPER
Table 2. Preparation of starting materials 6v–z and synthesis of condensed 7-hydroxypyrido[2,1-a]isoquinolinylium salts 1v–z by intramo-
lecular radical arylation.
Entry
4
5
X
R1
H
R2
H
R3
R4
R5
R6
6
6
X
R1
H
R2
H
R3
R4
R5
R6
1
1
Yield
Yield
[%][a,b]
[%][a,b]
1
2
3
4
5
4a 5l
4c 5l
4a 5m
4a 5n
4a 5o
C
C
C
C
N
(CH=CH)2
H
H
H
H
6v
6w
82
88
56
90
88
C
C
C
C
N
(CH=CH)2
H
H
H
H
1v
1w
47
43
50
45
27
OMe OMe (CH=CH)2
OMe OMe (CH=CH)2
H
H
H
H
H
H
Me
(CH=CH)2 (CH=CH)2 6y
(CH=CH)2 6z
H
(CH=CH)2 6x
H
H
H
H
H
H
Me
(CH=CH)2 (CH=CH)2 1y
(CH=CH)2 1z
H
(CH=CH)2 1x
–
H
H
H
[a] Yields for isolated products. [b] For detailed conditions see following section.
3
3
and bromine (1.76 g, 11 mmol) was added dropwise over 2 h. The
mixture was stirred at room temp. for 7 d (until starting material
could not be detected by TLC) and water (50 mL) was added. The
mixture was heated under reflux for 30 min, cooled to room tem-
perature, and two layers were separated. After separation of the
bottom layer, the remaining aqueous layer was extracted with
CH2Cl2. The combined organic extracts were dried, and the sol-
vents were evaporated to dryness. The crude product was purified
by flash chromatography [silica gel, hexanes/ethyl acetate (70:30)]
to give the pure compound 4c (2.40 g, 71%) as a white solid, m.p.
(d, JH,H = 8.2 Hz, 1 H), 8.68 (t, JH,H = 7.8 Hz, 1 H), 9.01 (d,
3JH,H = 6.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 11.2
(1 C, CH3), 26.0 (1 C, CH2), 120.0, 125.6, 128.0, 128.1, 130.7, 134.1,
134.8, 135.7, 146.8, 147.0, 161.1, 192.2 ppm. HRMS (ESI-TOF,
MeOH): calcd. for [C15H1579BrNO]+ 304.03370; found 304.03315.
1-[2-(2-Bromophenyl)-2-oxoethyl]-4-tert-butylpyridinium
Bromide
(6d): White solid (847 mg, 82%), m.p. 199–201 °C (EtOH). IR
(KBr): ν = 3049, 2968, 1709, 1643, 1469, 1333, 1210, 991, 759 cm–1.
˜
1H NMR (300 MHz, CD3OD): δ = 1.52 (s, 9 H, tBu), 7.61 (m, 2
3
3
H), 7.84 (d, JH,H = 7.6 Hz, 1 H), 8.07 (d, JH,H = 7.6 Hz, 1 H),
109–110 °C (MeOH). IR (NaCl): ν = 2939, 2844, 1592, 1513, 1264,
˜
3
3
8.29 (d, JH,H = 6.5 Hz, 2 H), 8.93 (d, JH,H = 6.5 Hz, 2 H) ppm.
13C NMR (75 MHz, CD3OD): δ = 28.9 [1 C, C(CH3)3], 36.4 (3 C,
3Me), 119.9, 124.1, 124.9, 127.8, 130.4, 130.7, 133.8, 145.4, 172.4,
191.8 ppm. HRMS (ESI-TOF, MeOH): calcd. for [C17H1979BrNO]+
332.06500; found 332.06314.
1217, 1150, 1018, 866 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.86
(s, 3 H, OMe), 3.89 (s, 3 H, OMe), 4.55 (s, 2 H, CH2), 7.02 (s, 1
H, Ar-H), 7.10 (s, 1 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 34.1 (1 C, CH2), 56.1 (1 C, OMe), 56.3 (1 C, OMe), 111.7,
113.1, 116.2, 129.7, 148.2, 152.1, 193.1 ppm. C10H10Br2O3 (338.00):
calcd. C 35.54, H 2.98; found C 35.92, H 2.99.
1-[2-(2-Bromophenyl)-2-oxoethyl]-4-phenylpyridinium Bromide (6e):
White solid (964 mg, 89%), m.p. 224–226 °C (EtOH). IR (KBr): ν
˜
General Method for the Preparation of Azinium Salts 6a–z: In a dry
Duran laboratory bottle (25 mL), to a mixture of 4 (2.5 mmol) in
dry acetone (5 mL), 5 (3 mmol) was added. The bottle was then
tightly closed, placed in an oven at 50 °C and maintained at this
temperature for 48 h. As long as the reaction was progressing, a
precipitate appeared. After 48 h, the mixture was allowed to reach
room temperature, and the solid was filtered off and washed with
EtOAc to yield the azinium salts 6 as solids. Crystallization from
suitable solvents furnished pure salts 6.
= 3023, 2946, 1702, 1641, 1208, 982, 765, 686 cm–1. 1H NMR
(300 MHz, [D6]DMSO): δ = 6.51 (s, 2 H, CH2 interchanged), 7.68
(m, 5 H), 7.86 (dd, JH,H = 7.8, 1.2 Hz, 1 H), 8.12 (m, 2 H), 8.19
3
(dd, JH,H = 7.6, 1.7 Hz, 1 H), 8.68 (d, JH,H = 6.9 Hz, 2 H), 9.12
3
(d, JH,H = 6.9 Hz, 2 H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ
= 66.0 (1 C, CH2), 119.4, 123.7, 127.5, 127.7, 129.1, 130.6, 131.8,
132.8, 133.8, 133.9, 134.2, 145.5, 154.8, 191.3 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C19H1579BrNO]+ 352.03370; found
352.03110.
1-[2-(2-Bromophenyl)-2-oxoethyl]-2-ethylpyridinium Bromide (6c):
White solid (732 mg, 76%), m.p. 191–192 °C (EtOH). IR (KBr): ν
1-[2-(2-Bromophenyl)-2-oxoethyl]-4-trifluoromethylpyridinium Bro-
˜
=
2991, 2896, 1718, 1629, 1218, 984, 774 cm–1. 1H NMR
mide (6f): White solid (839 mg, 79%), m.p. 225–227 °C (EtOH). IR
3
(300 MHz, CD3OD): δ = 1.46 (t, JH,H = 7.3 Hz, 3 H, CH3), 3.13
(q, JH,H = 7.3 Hz, 2 H, CH2), 6.46 (s, 2 H, CH2 interchanged),
(KBr): ν = 3024, 1998, 1469, 1322, 1142, 1082, 756 cm–1. 1H NMR
˜
3
(300 MHz, CD3OD): δ = 6.64 (s, 2 H, CH2 interchanged), 7.63 (m,
3
3
3
7.63 (m, 2 H), 7.85 (d, JH,H = 7.9 Hz, 1 H), 8.09 (m, 2 H), 8.22 2 H), 7.86 (d, JH,H = 7.3 Hz, 1 H), 8.12 (d, JH,H = 7.3 Hz, 1 H),
622
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 619–628

Radical Intramolecular Arylation of Pyridinium Salts
3
3
1
8.70 (d, JH,H = 5.0 Hz, 2 H), 9.44 (d, JH,H = 5.0 Hz, 2 H) ppm. 749 cm–1. H NMR (300 MHz, CD3OD): δ = 7.43 (ddd, J = 10.6,
13C NMR (50 MHz, [D6]DMSO): δ = 67.4 (1 C, CH2), 120.7 (q,
7.9, 2.6 Hz, 1 H), 7.69 (dd, J = 8.5, 2.6 Hz, 1 H), 8.22 (dd, J = 8.8,
1JC,F = 274.6 Hz, 1 C, CF3), 124.2 (q, JC,F = 3.1 Hz, 2 C), 127.5,
5.9 Hz, 1 H), 8.28 (app. t, JH,H = 7.3 Hz, 2 H), 8.79 (tt, JH,H
=
3
3
2
130.8, 133.4, 133.9, 134.4, 142.9 (q, JC,F = 36.0 Hz, 2 C), 143.2,
7.9, 1.2 Hz, 1 H), 9.07 (dd, JH,H = 6.7, 1.2 Hz, 2 H) ppm. 13C NMR
2
3
148.1, 190.1 ppm. HRMS (ESI-TOF, MeOH): calcd. for
(75 MHz, CD3OD): δ = 116.3 (d, JC,F = 21.7 Hz), 123.2 (d, JC,F
= 9.9 Hz), 123.5 (d, JC,F = 25.4 Hz), 129.2, 132.8 (d, JC,F
3.1 Hz), 134.5 (d, JC,F = 10.1 Hz), 147.9, 165.8 (d, JC,F
[C14H1079BrF3NO]+ 343.98979; found 343.98685.
=
=
2
4
3
1
1-[2-(2-Bromophenyl)-2-oxoethyl]-4-cyanopyridinium Bromide (6g):
White solid (774 mg, 81%), m.p. 248–250 °C (EtOH). IR (KBr): ν
257.3 Hz, 1 C, CF3), 190.7 ppm. HRMS (ESI-TOF, MeOH): calcd.
˜
for [C13H1079BrFNO]+ 293.99243; found 293.98861.
= 3088, 3008, 1988, 1705, 1637, 1504, 1459, 1325, 1222, 1192, 986,
764, 666 cm–1. H NMR (300 MHz, CD3OD): δ = 7.63 (m, 2 H),
1
1-[2-(2-Bromo-4-fluorophenyl)-2-oxoethyl]-2-methylpyridinium Bro-
3
3
mide (6m): White solid (807 mg, 83%), m.p. 214–216 °C (2-propa-
7.88 (d, JH,H = 7.6 Hz, 1 H), 8.03 (d, JH,H = 7.3 Hz, 1 H), 8.68
nol). IR (KBr): ν = 2939, 1708, 1592, 1577, 1225, 1050, 911 cm–1.
(d, JH,H = 6.6 Hz, 2 H), 9.26 (d, JH,H = 6.6 Hz, 2 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 67.6, 114.3, 119.7, 127.4, 127.6,
130.3, 130.9, 133.4, 134.1, 134.5, 147.0, 190.0 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C14H1079BrN2O]+ 300.99765; found
300.99526.
3
3
˜
1H NMR (300 MHz, CD3OD): δ = 2.85 (s, 3 H, Me), 7.44 (td, J
= 8.4, 2.6 Hz, 1 H), 7.70 (dd, J = 8.4, 2.6 Hz, 1 H), 8.08 (t, J =
7.0 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 8.24 (dd, J = 8.8, 5.9 Hz,
3
2 H), 8.64 (td, J = 7.9, 1.5 Hz, 1 H), 9.03 (d, JH,H = 6.2 Hz, 1 H)
ppm. 13C NMR (75 MHz, CD3OD): δ = 20.6 (1 C; Me), 116.3 (d,
1-[2-(2-Bromophenyl)-2-oxo-ethyl]-4-methoxypyridinium
(6h): Yellow solid (900 mg, 93%), m.p. Ͼ 171 °C (dec.) (EtOH). IR
Bromide
2JC,F = 22.3 Hz, 1 C), 123.0 (d, JC,F = 10.5 Hz, 1 C), 123.5 (d,
3
2JC,F = 25.4 Hz, 1 C), 126.9, 131.3, 134.1, 134.3 (d, 3JC,F = 9.3 Hz,
(KBr): ν = 3002, 1721, 1643, 1528, 1327, 1218, 1007, 853, 819, 760,
˜
1
1 C), 147.8, 147.9, 158.1, 165.8 (d, JC,F = 257.4 Hz, 1 C),
677, 640 cm–1. 1H NMR (300 MHz, CD3OD): δ = 4.24 (s, 3 H,
79
191.7 ppm. HRMS (ESI-TOF, MeOH): calcd. for [C14H12
-
OMe), 6.21 (s, 2 H, CH2 interchanged), 7.60 (m, 2 H), 7.68 (d,
BrFNO]+ 308.00808; found 308.00407.
3JH,H = 6.0 Hz, 2 H), 7.83 (d, JH,H = 7.3 Hz, 1 H), 8.02 (d, JH,H
3
3
= 7.6 Hz, 1 H), 8.79 (d, JH,H = 6.0 Hz, 2 H) ppm. 13C NMR
3
1-[2-(2-Bromo-4-fluorophenyl)-2-oxoethyl]-2-ethylpyridinium Bro-
mide (6n): White solid (725 mg, 72%), m.p. 190–192 °C (2-propa-
(75 MHz, CD3OD): δ = 59.0 (1 C, OMe), 114.4, 121.1, 129.1, 131.6,
135.0, 135.8, 137.0, 148.6, 173.4, 193.8 ppm. HRMS (ESI-TOF,
MeOH): calcd. for [C14H1379BrNO2]+ 306.01297; found 306.01089.
nol). IR (KBr): ν = 3035, 1707, 1593, 1223, 1051, 989 cm–1. 1H
˜
3
NMR (300 MHz, [D6]DMSO): δ = 1.28 (t, JH,H = 7.5 Hz, 3 H,
CH3), 3.04 (q, JH,H = 7.5 Hz, 2 H, CH2), 6.61 (s, 2 H, CH2), 7.60
(td, J = 8.5, 2.6 Hz, 1 H), 7.84 (dd, J = 8.8, 2.6 Hz, 1 H), 8.13 (t,
J = 6.9 Hz, 1 H), 8.20 (d, J = 7.9 Hz, 1 H), 8.39 (dd, J = 8.8,
3
1-[2-(2-Bromophenyl)-2-oxoethyl]-2,3-dimethylpyridinium Bromide
(6i): White solid (741 mg, 77%), m.p. 210–211 °C (EtOH). IR
(KBr): ν = 2982, 2900, 1712, 1502, 1470, 1222, 989, 776 cm–1. H
1
˜
3
5.9 Hz, 1 H), 8.68 (dd, J = 7.8, 0.9 Hz, 1 H), 9.14 (d, JH,H
=
NMR (300 MHz, CD3OD): δ = 2.66 (s, 3 H, Me), 2.76 (s, 3 H,
5.6 Hz) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 11.6 (1 C,
3
3
Me), 7.36 (m, 2 H), 7.58 (d, JH,H = 7.3 Hz, 1 H), 7.67 (t, JH,H
=
2
CH3), 24.8 (1 C, CH2), 64.1 (1 C, CH2), 114.6 (d, JC,F = 21.1 Hz,
6.7 Hz, 1 H), 7.83 (d, 3JH,H = 7.6 Hz, 1 H), 8.24 (d, 3JH,H = 7.6 Hz,
3
2
1 C), 121.0 (d, JC,F = 9.9 Hz, 1 C), 121.6 (d, JC,F = 24.8 Hz, 1
1 H), 8.62 (d, JH,H = 5.9 Hz, 1 H) ppm. 13C NMR (75 MHz,
3
C), 125.0, 127.3, 131.0, 132.9 (d, 3JC,F = 9.9 Hz, 1 C), 146.1, 146.3,
CD3OD): δ = 17.7 (1 C, Me), 20.0 (1 C, Me), 121.0, 126.0, 129.2,
131.6, 135.2, 135.9, 137.0, 140.6, 145.6, 148.1, 157.1, 193.3 ppm.
HRMS (ESI-TOF, MeOH): calcd. for [C15H1579BrNO]+ 304.03370;
found 304.03315.
1
159.8, 163.2 (d, JC,F = 256.2 Hz, 1 C), 190.8 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C15H1479BrFNO]+ 322.02373; found
322.01925.
1-[2-(2-Bromo-4-fluorophenyl)-2-oxoethyl]-3,5-dimethylpyridinium
Bromide (6o): White solid (846 mg, 84%), m.p. 225–227 °C (2-pro-
1-[2-(2-Bromophenyl)-2-oxoethyl]-3,5-dimethylpyridinium Bromide
(6j): White solid (866 mg, 90%), m.p. 220–222 °C (EtOH). IR
panol). IR (KBr): ν = 3001, 2934, 1727, 1589, 1480, 1343, 1228,
˜
1
831 cm–1. H NMR (300 MHz, CD3OD): δ = 2.62 (s, 6 H, 2Me),
(KBr): ν = 2993, 2935, 2803, 1720, 1426, 1352, 1211, 1063, 770,
˜
669, 607 cm–1. 1H NMR (300 MHz, CD3OD): δ = 2.61 (s, 6 H,
7.43 (td, J = 8.4, 2.6 Hz 1 H), 7.68 (dd, J = 8.5, 2.6 Hz, 1 H), 8.23
(dd, J = 8.8, 5.9 Hz, 1 H), 8.80 (br. s, 2 H), 8.47 (br. s, 1 H) ppm.
13C NMR (75 MHz, CD3OD): δ = 18.3 (2 C, 2Me), 116.2 (d, 2JC,F
2Me), 6.36 (s, 2 H, CH2 interchanged), 7.60 (m, 2 H), 7.83 (d, 3JH,H
3
= 7.3 Hz, 1 H), 8.08 (d, JH,H = 6.7 Hz, 1 H), 8.44 (br. s, 1 H, Ar-
H), 8.77 (br. s, 2 H, Ar-H) ppm. 13C NMR (75 MHz, CD3OD): δ
= 18.3 (2 C, 2Me), 68.7 (1 C, CH2), 121.2, 129.1, 131.8, 135.1,
135.9, 136.7, 140.1, 144.2, 148.8, 192.9 ppm. HRMS (ESI-TOF,
MeOH): calcd. for [C15H1579BrNO]+ 304.03370; found 304.03127.
3
2
= 21.7 Hz, 1 C), 123.3 (d, JC,F = 10.0 Hz, 1 C), 123.4 (d, JC,F
=
3
25.4 Hz, 1 C), 133.9, 134.5 (d, JC,F = 9.9 Hz), 139.2, 144.0, 148.8,
1
165.7 (d, JC,F = 257.4 Hz, 1 C), 191.4 ppm. HRMS (ESI-TOF,
MeOH): calcd. for [C15H1479BrFNO]+ 322.02373; found 322.02239.
1-[2-(2-Bromophenyl)-2-oxoethyl]-2,3,5-trimethylpyridinium
Bro-
1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-pyridinium
mide (6p): White solid (928 mg, 89%), m.p. Ͼ 239 °C (dec.)
Bro-
mide (6k): White solid (768 mg, 77%), m.p. 234–235 °C (EtOH).
IR (KBr): ν = 2985, 1713, 1508, 1423, 1352, 1221, 773, 605 cm–1.
˜
(EtOH). IR (KBr): ν = 3034, 1698, 1342, 1267, 1201, 1171,
˜
1H NMR (300 MHz, CD3OD): δ = 2.54 (s, 3 H, Me), 2.61 (s, 3 H,
1060 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 3.90 (s, 6 H,
2MeO), 6.52 (s, 2 H, CH2), 7.36 (s, 1 H), 7.66 (s, 1 H), 8.29 (app.
t, 3JH,H = 5.7 Hz, 2 H), 8.74 (t, 3JH,H = 7.6 Hz, 1 H), 9.05 (d, 3JH,H
= 4.1 Hz, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 55.9 (2
C, 2MeO), 66.8 (1 C, CH2), 112.1, 113.5, 117.0, 125.3, 127.4, 145.6,
145.9, 147.2, 152.2, 189.3 ppm. HRMS (ESI-TOF, MeOH): calcd.
for [C15H1579BrNO3]+ 336.02298; found 336.02072.
Me), 2.70 (s, 3 H, Me), 6.43 (s, 2 H, CH2 interchanged), 7.62 (m,
3
3
2 H), 7.84 (d, JH,H = 7.6 Hz, 1 H), 8.12 (d, JH,H = 7.0 Hz, 1 H),
8.37 (br. s, 1 H, Ar-H), 8.81 (br. s, 1 H, Ar-H) ppm. 13C NMR
(75 MHz, CD3OD): δ = 17.2 (1 C, Me), 17.8 (1 C, Me), 19.9 (1 C,
Me), 120.9, 129.2, 131.6, 135.1, 135.8, 137.0, 137.2, 139.6, 144.8,
149.0, 154.0, 193.4 ppm. HRMS (ESI-TOF, MeOH): calcd. for
[C16H1779BrNO]+ 318.04880; found 318.05019.
1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-4-phenylpyridinium
1-[2-(2-Bromo-4-fluorophenyl)-2-oxoethyl]-pyridinium Bromide (6l):
Bromide (6q): White solid (1.171 g, 95%), m.p. Ͼ 255 °C (dec.)
White solid (797 mg, 85%), m.p. 224–225 °C (2-propanol). IR
(EtOH). IR (KBr): ν = 2999, 2945, 1641, 1562, 1342, 1268, 1202,
˜
1
(KBr): ν = 3013, 2904, 1702, 1591, 1574, 1492, 1216, 985, 814, 1174, 1058, 764 cm–1. H NMR (200 MHz, [D6]DMSO): δ = 3.90
˜
Eur. J. Org. Chem. 2011, 619–628
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
623

R. R. Castillo, C. Burgos, J. J. Vaquero, J. Alvarez-Builla
(s, 3 H, OMe), 3.91 (s, 3 H, OMe), 6.49 (s, 2 H, CH2), 7.37 (br. s, 1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-quinolinium Bro-
FULL PAPER
3
1 H), 7.69 (m, 4 H), 8.14 (m, 2 H), 8.66 (d, JH,H = 6.8 Hz, 2 H),
mide (6w): White solid (1.027 g, 88%), m.p. Ͼ 257 °C (dec.)
9.07 (d, JH,H = 6.8 Hz, 2 H) ppm. 13C NMR (75 MHz, [D6]-
(EtOH). IR (KBr): ν = 2911, 1698, 1587, 1511, 1376, 1349, 1264,
3
˜
DMSO): δ = 55.8 (1 C, OMe), 55.9 (1 C, OMe), 66.1 (1 C, CH2),
112.1, 113.5, 117.1, 123.8, 125.4, 127.8, 129.2, 131.8, 133.0 145.6,
147.3, 152.2, 154.9, 189.5 ppm. HRMS (ESI-TOF, MeOH): calcd.
for [C21H1979BrNO3]+ 412.05428; found 412.05427.
1205, 1172, 1050 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 3.90
(s, 3 H, OMe), 3.95 (s, 3 H, OMe), 7.02 (s, 2 H, CH2), 7.38 (s, 1
3
H), 7.84 (s, 1 H), 8.07 (app. t, JH,H = 7.6 Hz, 1 H), 8.26 (app. t,
3
3JH,H = 8.1 Hz, 1 H), 8.34 (app. t, JH,H = 7.0 Hz, 1 H), 8.42 (d,
3
3
3JH,H = 8.8 Hz, 1 H), 8.56 (d, JH,H = 7.9 Hz, 1 H), 9.46 (d, JH,H
1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-4-trifluoromethyl-
pyridinium Bromide (6r): White solid (994 mg, 82%), m.p. Ͼ 237 °C
= 8.2 Hz, 1 H), 9.61 (d, JH,H = 5.6 Hz, 1 H) ppm. 13C NMR
3
(75 MHz, [D6]DMSO): δ = 55.9 (1 C, OMe), 56.0 (1 C, OMe), 63.9
(1 C, CH2), 112.0, 113.7, 117.0, 118.6, 121.7, 125.6, 128.9, 129.4,
130.1, 135.3, 138.0, 147.2, 148.1, 150.2, 152.2, 189.4 ppm. HRMS
(ESI-TOF, MeOH): calcd. for [C19H1779BrNO3]+ 386.03863; found
386.03365.
(dec.) (EtOH). IR (KBr): ν = 3027, 2961, 2848, 1691, 1596, 1513,
˜
1465, 1325, 1268, 1167, 1054 cm–1 1H NMR (300 MHz, [D6]-
.
DMSO): δ = 3.89 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 6.80 (s, 2 H,
CH2), 7.35 (s, 1 H), 7.75 (s, 1 H), 8.85 (d, 3JH,H = 5.9 Hz, 2 H), 9.50
(d, JH,H = 5.9 Hz, 2 H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ
3
= 55.5 (1 C, OMe), 55.6 (1 C, OMe), 67.1 (1 C, CH2), 112.1, 113.3, 1-[2-(2-Bromophenyl)-2-oxoethyl]-3-methylisoquinolinylium Bromide
1
3
116.8, 120.7 (q, JC,F = 274.6 Hz, 1 C, CF3), 124.7, 123.9 (q, JC,F
(6x): White solid (590 mg, 56%), m.p. 198–200 °C (EtOH). IR
= 3.1 Hz, 2 C), 142.6 (q, 2JC,F = 35.3 Hz, 2 C), 146.9, 147.7, 152.0, (KBr): ν = 2998, 2889, 1709, 1645, 1430, 1224, 990, 779, 768 cm–1.
˜
1 8 8 . 0 p p m . H R M S ( E S I - T O F, M e O H ) : c a l c d . f o r
1H NMR (300 MHz, CD3OD): δ = 2.86 (s, 3 H, Me), 7.59 (m, 2
[C16H1479BrF3NO3]+ 404.01037; found 404.00728.
H), 7.80 (d, JH,H = 7.9 Hz, 1 H), 7.98 (dt, JH,H = 8.2, 7.9 Hz, 1
3
3
H), 8.15 (d, JH,H = 7.3 Hz, 1 H), 8.22 (m, 2 H), 8.43 (m, 2 H),
1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-4-methoxypyrid-
inium Bromide (6s): White solid (961 mg, 86 %), m.p. Ͼ 180 °C
10.09 (s, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 19.8 (1 C,
Me), 121.0, 127.5, 127.7, 127.8, 129.2, 131.2, 131.7, 131.9, 135.2,
135.8, 137.0, 138.9, 140.3, 146.1, 153.2, 193.9 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C18H1579BrNO]+ 340.03315; found
340.03275.
(dec.) (EtOH). IR (KBr): ν = 3007, 1689, 1646, 1564, 1528, 1343,
˜
1271, 1205, 1170, 1057, 1002 cm–1 1H NMR (300 MHz, [D6]-
.
DMSO): δ = 3.88 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 4.14 (s, 3 H,
OMe), 6.43 (s, 2 H, CH2), 7.33 (s, 1 H), 7.72 (s, 1 H), 7.77 (d, 3JH,H
= 7.0 Hz, 2 H), 8.91 (d, JH,H = 7.0 Hz, 2 H) ppm. 13C NMR
1-[2-(2-Bromophenyl)-2-oxoethyl]-phenanthridinium Bromide (6y):
3
(75 MHz, [D6]DMSO): δ = 55.8 (1 C, OMe), 55.9 (1 C, OMe), 57.8
(1 C, OMe), 64.9 (1 C, CH2), 111.8, 112.7, 113.4, 116.9, 125.6,
146.8, 147.2, 152.0, 170.5, 190.1 ppm. HRMS (ESI-TOF, MeOH):
calcd. for [C16H1779BrNO4]+ 366.03355; found 366.03147.
White solid (1.029 g, 90%), m.p. 249–250 °C (EtOH). IR (KBr): ν
˜
= 3003, 2880, 1712, 1625, 1353, 1219, 984, 774, 751 cm–1. 1H NMR
3
(300 MHz, [D6]DMSO): δ = 6.10 (s, 2 H), 6.61 (t, JH,H = 7.6 Hz,
3
3
1 H), 6.75 (t, JH,H = 7.6 Hz, 1 H), 6.91 (d, JH,H = 7.6 Hz, 1 H),
3
7.13 (m, 3 H), 7.39 (d, JH,H = 7.9 Hz, 1 H), 7.50 (m, 2 H), 7.63
1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-3,5-dimethylpyr-
idinium Bromide (6t): White solid (1.012 g, 91%), m.p. Ͼ 247 °C
(d, JH,H = 8.2 Hz, 1 H), 8.23 (m, 2 H), 9.63 (s, 1 H) ppm. 13C
3
NMR (75 MHz, [D6]DMSO): δ = 64.1 (1 C, CH2), 119.3, 119.5,
122.6, 122.9, 124.5, 124.9, 127.6, 129.9, 130.2, 130.5, 131.7, 132.6,
133.3, 133.8, 134.2, 134.3, 134.6, 138.4, 156.5, 191.9 ppm. HRMS
(ESI-TOF, MeOH): calcd. for [C21H1579BrNO]+ 376.03315; found
376.03087.
(dec.) (EtOH). IR (KBr): ν = 2995, 2925, 1723, 1500, 1259, 1210,
˜
1169 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 2.49 (s, 6 H,
2Me), 3.88 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 6.44 (s, 2 H, CH2),
7.35 (s, 1 H), 7.69 (s, 1 H), 8.45 (br. s, 1 H), 8.85 (br. s, 2 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 17.2 (2 C, 2Me), 55.8 (1 C,
OMe), 55.9 (1 C, OMe), 66.4 (1 C, CH2), 112.0, 113.5, 117.0, 125.4,
1-[2-(2-Bromophenyl)-2-oxoethyl]-phthalazin-2-ium Bromide (6z):
137.1, 142.4, 146.7, 147.3, 152.2, 189.4 ppm. HRMS (ESI-TOF, Yellow solid (898 mg, 88%), m.p. 235–237 °C (EtOH). IR (KBr): ν
˜
MeOH): calcd. for [C17H1979BrNO3]+ 364.05428; found 364.05294.
= 3074, 3011, 2952, 2867, 2810, 1720, 1393, 1346, 1225, 996,
761 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 6.69 (s, 2 H, CH2),
7.65 (m, 2 H), 7.87 (d, 3JH,H = 7.9 Hz, 1 H), 8.14 (d, 3JH,H = 7.3 Hz,
1-[2-(2-Bromo-4,5-dimethoxyphenyl)-2-oxoethyl]-2,3,5-trimethyl-
pyridinium Bromide (6u): White solid (907 mg, 79%), m.p. Ͼ 225 °C
3
1 H), 8.49 (app. t, JH,H = 7.3 Hz, 1 H), 8.65 (m, 2 H), 8.77 (d,
(dec.) (EtOH). IR (KBr): ν = 2979, 1698, 1509, 1344, 1261, 1203,
˜
3JH,H = 7.9 Hz, 1 H), 10.21 (s, 1 H), 10.73 (s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 69.5 (1 C, CH2), 119.1, 126.7, 126.9,
127.6, 128.1, 130.3, 133.8, 134.2, 134.4, 135.7, 136.1, 139.4, 153.0,
154.4, 191.4 ppm. HRMS (ESI-TOF, MeOH): calcd. for
[C16H1279BrN2O]+ 327.01275; found 327.01077.
1171 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 2.42 (s, 3 H, Me),
2.51 (s, 3 H, Me), 2.57 (s, 3 H, Me), 3.89 (s, 3 H, OMe), 3.94 (s, 3
H, OMe), 6.63 (s, 2 H, CH2), 7.35 (s, 1 H), 7.78 (s, 1 H), 8.39 (br.
s, 1 H), 8.95 (br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 17.1 (1 C, Me), 17.9 (1 C, Me), 19.9 (1 C, Me), 57.1 (1 C, OMe),
57.3 (1 C, OMe), 66.4 (1 C, CH2), 112.8, 114.6, 118.1, 127.0, 135.4, General Method for the Preparation of Compounds 1a–z by Radical
138.3, 144.0, 148.0, 148.5, 153.3, 153.4, 191.0 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C18H2179BrNO3]+ 378.06993; found
378.06549.
Cyclization: A solution of TTMSS (0.498 g, 2 mmol) and AIBN
(0.328 g, 2 mmol) in dry m-xylene (20 mL) was added dropwise by
a syringe pump during 14 h to a stirred solution of the appropriate
azinium salt 6 (1 mmol) in dry MeCN (70 mL), at reflux under
an atmosphere of dry argon. Stirring was maintained at the same
temperature for a further 18 h, after which the starting material
had been consumed (TLC analysis). The solution was concen-
trated, and the crude mixture was triturated with toluene. Filtration
and crystallization from suitable solvents furnished pure salts 1.
1-[2-(2-Bromophenyl)-2-oxoethyl]-quinolinium Bromide (6v): White
solid (835 mg, 82%), m.p. 225–227 °C (EtOH). IR (KBr): ν = 3028,
˜
1
2954, 2780, 2664, 1711, 1531, 1226, 985, 802, 767 cm–1. H NMR
3
(300 MHz, CD3OD): δ = 7.65 (m, 2 H), 7.89 (d, JH,H = 7.9 Hz, 1
3
H), 8.32 (m, 3 H), 8.12 (m, 2 H), 8.54 (d, JH,H = 8.2 Hz, 1 H),
3
3
9.41 (d, JH,H = 8.2 Hz, 1 H), 9.51 (d, JH,H = 5.9 Hz, 1 H) ppm.
13C NMR (75 MHz, CD3OD): δ = 119.8, 121.3, 123.1, 129.2, 131.5, 7-Hydroxypyrido[2,1-a]isoquinolinylium Bromide (1a): Brown solid
131.6, 131.7, 132.1, 135.3, 136.1, 137.1, 137.6, 140.4, 150.3, 151.9, (115 mg, 42%), m.p. Ͼ 271 °C (dec.) (acetonitrile/toluene). IR
193.0 ppm. HRMS (ESI-TOF, MeOH): calcd. for [C17H1379Br- (KBr): ν = 3291, 3047, 2583, 1645, 1481, 1361, 775 cm–1. 1H NMR
˜
NO]+ 326.01750; found 326.01538.
(300 MHz, CD3OD): δ = 8.12 (m, 3 H), 8.42 (m, 2 H), 8.54 (d,
624
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 619–628

Radical Intramolecular Arylation of Pyridinium Salts
3
3
3JH,H = 7.7 Hz, 1 H), 9.06 (d, JH,H = 7.9 Hz, 1 H), 9.25 (d, JH,H
(343.9636): calcd. C 48.86, H 2.64, N 4.07; found C 49.10, H 2.96,
N 3.99.
= 6.6 Hz, 1 H), 9.32 (d, JH,H = 8.6 Hz, 1 H) ppm. 13C NMR
3
(75 MHz, CD3OD): δ = 114.1, 123.9, 124.0, 125.4, 126.5, 126.8,
128.8, 132.6, 134.7, 137.6, 138.5, 140.5, 151.9 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C13H10NO]+ 196.0762; found 196.0774.
C13H10BrNO (276.13): calcd. C 56.55, H 3.65, N 5.07; found C
56.16, H 4.20, N 4.88.
2-Cyano-7-hydroxypyrido[2,1-a]isoquinolinylium Bromide (1g):
Brown solid (90 mg, 12%), m.p. Ͼ 252 °C (dec.) (acetonitrile). IR
(KBr): ν = 3291, 3047, 2583, 2359, 1645, 1481, 1361, 1266, 775,
˜
721 cm–1. H NMR (300 MHz, CD3OD): δ = 8.16 (m, 2 H), 8.20
1
3
3
(d, JH,H = 9.1 Hz, 1 H), 8.25 (s, 1 H), 8.40 (d, JH,H = 8.1 Hz, 1
H), 8.54 (d, JH,H = 7.8 Hz, 1 H), 9.23 (m, 2 H) ppm. 13C NMR
3
7-Hydroxy-4-methylpyrido[2,1-a]isoquinolinylium Bromide (1b):
White solid (113 mg, 39%), m.p. Ͼ 240 °C (dec.) (acetonitrile). IR
(75 MHz, CD3OD): δ = 116.9, 118.3, 124.2, 126.7, 126.9, 128.1 (1
C, CN) 129.8, 132.5, 133.6, 135.0, 141.2, 144.4, 149.6, 168.1 ppm.
HRMS (ESI-TOF, MeOH): calcd. for [C14H9N2O]+ 221.0715;
found 221.0714. C14H9BrN2O (300.9715): calcd. C 55.84, H 3.01,
N 9.30; found C 56.02, H 2.97, N 9.54.
(KBr): ν = 3319, 3074, 1643, 1482, 1352, 1084, 780 cm–1. 1H NMR
˜
(300 MHz, CD3OD): δ = 3.10 (s, 3 H, Me), 8.30 (s, 1 H), 8.13 (m,
3
3 H), 8.35 (app. t, JH,H = 7.7 Hz, 1 H), 8.55 (dd, JH,H = 7.6,
3
1.7 Hz, 1 H), 9.09 (dd, JH,H = 7.6, 1.3 Hz, 1 H), 9.31 (d, JH,H
=
9.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 21.6 (1 C,
Me), 109.6, 122.4, 123.8, 126.7, 127.1, 127.6, 128.1, 132.8, 134.6,
136.8, 141.2, 146.4, 152.2 ppm. MS (API-ES, Pos): m/z = 210.1
[C14H12NO]+, [M]+. C14H12BrNO (289.9919): calcd. C 57.95, H
4.17, N 4.83; found C 58.09, H 4.25, N 4.66.
2,7-Dihydroxypyrido[2,1-a]isoquinolinylium Bromide (1h): Brown
solid (102 mg, 35%), m.p. Ͼ 290 °C (dec.) (acetonitrile/EtOH). IR
(KBr): ν = 3069, 1655, 1480, 1284, 1088, 841 cm–1. 1H NMR
˜
(300 MHz, CD3OD): δ = 7.48 (dd, JH,H = 7.3, 2.4 Hz, 1 H), 8.03
3
(m, 3 H), 8.35 (d, JH,H = 2.4 Hz, 1 H), 8.41 (d, JH,H = 7.9 Hz, 1
3
3
4-Ethyl-7-hydroxypyrido[2,1-a]isoquinolinylium Bromide (1c): Pale
yellow solid (140 mg, 46%), m.p.Ͼ299 °C (dec.) (acetonitrile). IR
H), 8.78 (d, JH,H = 8.2 Hz, 1 H), 8.96 (d, JH,H = 7.3 Hz, 1 H)
ppm. 13C NMR (75 MHz, CD3OD): δ = 107.3, 116.1, 123.9, 126.0,
126.2, 129.0, 131.9, 133.1, 134.4, 140.8, 143.4, 148.5, 166.5 ppm.
HRMS (ESI-TOF, MeOH): calcd. for [C13H10NO2]+ 226.0868;
found 226.0868. C13H10BrNO2 (291.9712): calcd. C 53.45, H 3.45,
N 4.79; found C 53.06, H 3.68, N 4.86.
1
(KBr): ν = 3127, 2885, 1643, 1482, 1335, 1084, 803, 781 cm–1. H
˜
NMR (300 MHz, CD3OD): δ = 1.63 (t, 3JH,H = 7.3 Hz, 3 H, CH3),
3.44 (q, JH,H = 7.3 Hz, 2 H, CH2), 8.12 (m, 3 H), 8.39 (m, 2 H),
3
3
3
8.53 (d, JH,H = 7.8 Hz, 1 H), 9.08 (d, JH,H = 7.9 Hz, 1 H), 9.30
(d, JH,H = 8.8 Hz, 1 H) ppm. 13C NMR (50 MHz, CD3OD): δ =
3
7-Hydroxy-3,4-dimethylpyrido[2,1-a]isoquinolinylium Bromide (1i):
Pale brown solid (110 mg, 36%), m.p. Ͼ 300 °C (dec.) (acetonitrile/
11.3 (1 C, CH3), 28.1 (1 C, CH2), 109.1, 122.2, 122.3, 123.7, 125.1,
126.8, 128.0, 132.7, 134.5, 136.9, 141.2, 150.6, 152.1 ppm. MS
(API-ES, Pos): m/z = 224.2 [C15H14NO]+, [M]+. C15H14BrNO
(304.0075): calcd. C 59.23, H 4.64, N 4.60; found C 59.56, H 4.62,
N 4.36.
toluene). IR (KBr): ν = 3425, 2865, 1642, 1606, 1481, 1334, 1067,
˜
782 cm–1. 1H NMR (300 MHz, CD3OD): δ = 2.78 (s, 3 H), 3.01 (s,
3
3 H), 8.13 (m, 2 H), 8.30 (d, JH,H = 9.1 Hz, 1 H), 8.35 (s, 1 H),
8.54 (dd, JH,H = 7.9, 1.8 Hz, 1 H), 9.05 (dd, JH,H = 7.6, 1.8 Hz, 1
2-tert-Butyl-7-hydroxypyrido[2,1-a]isoquinolinylium Bromide (1d):
Yellow solid (93 mg, 39%), m.p. Ͼ 300 °C (dec.) (acetonitrile/tolu-
3
H), 9.19 (d, JH,H = 9.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
CD3OD): δ = 17.7 (1 C, Me), 20.7 (1 C, Me), 109.6, 115.3, 121.3,
123.7, 126.4, 127.6, 127.7, 132.7, 134.2, 135.9, 139.2, 144.5,
152.1 ppm. MS (API-ES, Pos): m/z = 224.2 [C15H14NO]+, [M]+.
C15H14BrNO (304.0075): calcd. C 59.23, H 4.64, N 4.60; found C
59.10, H 4.71, N 4.81.
ene). IR (KBr): ν = 3383, 2738, 2536, 1644, 1466, 1262, 762 cm–1.
˜
1H NMR (300 MHz, CD3OD): δ = 1.60 (s, 9 H, 3Me), 8.13 (m, 3
H), 8.32 (s, 1 H), 8.50 (d, 3JH,H = 7.6 Hz, 1 H), 9.12 (m, 3 H) ppm.
13C NMR (75 MHz, CD3OD): δ = 30.5 [1 C, C(CH3)3], 37.3 (3 C,
3Me), 113.4, 119.5, 123.9, 126.6, 126.8, 129.0, 132.5, 134.6, 135.6,
138.2, 140.4, 151.4, 163.1 ppm. MS (API-ES, Pos): m/z = 252.1
[C17H18NO]+, [M]+. C17H18BrNO (332.9388): calcd. C 61.46, H
5.46, N 4.22; found C 61.60, H 5.33, N 3.99.
7-Hydroxy-1,3-dimethylpyrido[2,1-a]isoquinolinylium Bromide (1j):
Pale brown solid (134 mg, 44%), m.p. Ͼ 300 °C (acetonitrile/tolu-
ene). IR (KBr): ν = 3431, 3051, 2715, 1646, 1602, 1479, 1429, 1338,
˜
772 cm–1. 1H NMR (300 MHz, CD3OD): δ = 2.64 (s, 3 H, Me),
3.22 (s, 3 H, Me), 8.07 (m, 2 H), 8.20 (br. s, 1 H), 8.28 (br. s, 1 H),
8.52 (dd, JH,H = 8.1, 1.6 Hz, 1 H), 9.07 (m, 2 H) ppm. 13C NMR
(50 MHz, CD3OD): δ = 17.9 (1 C, Me), 26.2 (1 C, Me), 114.4,
123.6, 127.8, 129.3, 129.8, 131.4, 133.4, 135.6, 136.5, 137.1, 138.7,
143.5, 151.1 ppm. HRMS (ESI-TOF, MeOH): calcd. for
[C15H14NO]+ 224.1075; found 224.1093. C15H14BrNO (304.0075):
calcd. C 59.23, H 4.64, N 4.60; found C 58.93, H 4.65, N 4.62.
7-Hydroxy-2-phenylpyrido[2,1-a]isoquinolinylium Bromide (1e):
Bright yellow solid (116 mg, 33%), m.p. Ͼ 300 °C (acetonitrile/tol-
1
uene). IR (KBr): ν = 2822, 1643, 1467, 1090, 770 cm–1. H NMR
˜
(300 MHz, CD3OD): δ = 7.68 (m, 3 H), 8.36 (s, 1 H), 8.15 (m, 4
H), 8.40 (dd, JH,H = 7.0, 2.0 Hz, 1 H), 8.54 (dd, JH,H = 7.0, 2.0 Hz,
1 H), 9.23 (m, 2 H), 9.45 (d, JH,H = 1.8 Hz, 1 H) ppm. 13C NMR
(75 MHz, CD3OD): δ = 113.5, 120.0, 123.3, 123.9, 126.8, 127.0,
128.9, 130.8, 132.2, 132.4, 132.5, 134.3, 134.6, 136.3, 138.6, 149.4,
151.5 ppm. HRMS (ESI-TOF, MeOH): calcd. for [C19H14NO]+
272.1075; found 272.1065. C19H14BrNO (352.0075): calcd. C 64.79,
H 4.01, N 3.98; found C 64.54, H 4.12, N 3.95.
7-Hydroxy-1,3,4-trimethylpyrido[2,1-a]isoquinolinylium
Bromide
(1k): Pale brown solid (159 mg, 50%), m.p. Ͼ 296 °C (dec.) (aceto-
nitrile). IR (KBr): ν = 3122, 2886, 2554, 1639, 1602, 1476, 1424,
˜
1
1071 cm–1. H NMR (300 MHz, CD3OD): δ = 2.73 (s, 3 H, Me),
7-Hydroxy-2-trifluoromethylpyrido[2,1-a]isoquinolinylium Bromide
(1f): Yellow solid (124 mg, 36%), m.p. Ͼ 238 °C (dec.) (acetoni-
2.98 (s, 3 H, Me), 3.21 (s, 3 H, Me), 8.08 (m, 2 H), 8.24 (s, 1 H),
8.30 (s, 1 H), 8.53 (d, 3JH,H = 7.9 Hz, 1 H), 9.02 (d, 3JH,H = 8.2 Hz,
1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 20.3 (1 C, Me), 26.0
(2 C, 2Me), 110.1, 123.3, 123.4, 128.3, 128.4, 130.2, 131.2, 133.4,
134.7, 140.1, 143.2, 143.3, 151.4 ppm. MS (API-ES, Pos): m/z =
238.0 [C16H16NO]+, [M]+. C16H16BrNO (318.0232): calcd. C 60.39,
H 5.07, N 4.40; found C 60.61, H 5.02, N 4.31.
trile). IR (KBr): ν = 3374, 3027, 1604, 1461, 1353, 1141, 1101, 831,
˜
1
784 cm–1. H NMR (300 MHz, CD3OD): δ = 8.24 (m, 2 H), 8.33
3
3
(d, JH,H = 7.0 Hz, 1 H), 8.62 (m, 2 H), 9.25 (d, JH,H = 7.4 Hz, 1
H), 9.49 (d, 3JH,H = 7.4 Hz, 1 H), 9.65 (br. s, 1 H) ppm. 13C NMR
3
(50 MHz, [D6]DMSO): δ = 113.9, 118.8 (q, JC,F = 3.1 Hz, 1 C),
3
1
120.2 (q, JC,F = 3.7 Hz, 1 C), 121.8, 121.9 (q, JC,F = 274.2 Hz, 1
C, CF3), 126.0, 127.0, 127.6, 131.1, 133.0 (q, 2JC,F = 35.2 Hz, 1 C),
133.7, 134.6, 138.7, 151.4 ppm. HRMS (ESI-TOF, MeOH): calcd.
for [C14H9F3NO]+ 264.0636; found 264.0679. C14H9BrF3NO
10-Fluoro-7-hydroxypyrido[2,1-a]isoquinolinylium Bromide (1l):
Brown solid (115 mg, 39%), m.p. Ͼ 238 °C (dec.) (acetonitrile/tolu-
ene). IR (KBr): ν = 3040, 1644, 1611, 1472, 1425, 1358, 1217,
˜
Eur. J. Org. Chem. 2011, 619–628
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
625

R. R. Castillo, C. Burgos, J. J. Vaquero, J. Alvarez-Builla
FULL PAPER
1102 cm–1. 1H NMR (300 MHz, CD3OD): δ = 7.96 (td, J = 8.2,
256.0979. C15H14BrNO3 (335.0157): calcd. C 53.59, H 4.20, N 4.17;
2.1 Hz, 1 H), 8.11 (app. t, J = 6.8 Hz, 1 H), 8.43 (m, 2 H), 8.57 found C 53.29, H 4.47, N 4.01.
(dd, J = 9.1, 5.6 Hz, 1 H), 8.82 (dd, J = 10.3, 2.1 Hz, 1 H, dd, 1
7-Hydroxy-9,10-dimethoxy-2-phenylpyrido[2,1-a]isoquinolinylium
Bromide (1q): Bright yellow solid (181 mg, 44%), m.p. Ͼ 265 °C
H), 9.29 (m, 2 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 112.1
(d, JC,F = 26.0 Hz, 1 C), 113.9, 123.7 (d, JC,F = 24.8 Hz, 1 C),
2
2
(dec.) (2-propanol). IR (KBr): ν = 3435, 3063, 2818, 1644, 1608,
˜
3
3
124.5, 125.8, 126.0, 127.3 (d, JC,F = 10.2 Hz, 1 C), 129.1 (d, JC,F
1
1525, 1470, 1424, 1265, 1213 cm–1. H NMR (300 MHz, CD3OD):
4
= 9.9 Hz, 1 C), 137.7, 138.7, 139.8 (d, JC,F = 4.7 Hz, 1 C), 151.7,
δ = 4.12 (s, 3 H, OMe), 4.21 (s, 3 H, OMe), 7.66 (m, 3 H), 7.79 (s,
1 H), 8.14 (dd, JH,H = 7.6, 1.5 Hz, 2 H), 8.22 (dd, JH,H = 7.0,
1
165.3 (d, JC,F = 250.7 Hz, 1 C) ppm. MS (API-ES, Pos): m/z =
214.0 [C13H9FNO]+, [M]+. C13H9BrFNO (292.9852): calcd. C
53.09, H 3.08, N 4.76; found C 52.81, H 3.12, N 4.77.
3
2.0 Hz, 1 H), 8.28 (s, 1 H), 8.36 (s, 1 H), 9.11 (d, JH,H = 7.0 Hz,
4
1 H), 9.25 (d, JH,H = 1.8 Hz, 1 H) ppm. 13C NMR (75 MHz,
CD3OD): δ = 57.0 (1 C, OMe), 57.4 (1 C, OMe), 103.3, 106.6,
112.6, 119.7, 122.2, 125.2, 127.5, 129.0, 130.1, 130.7, 131.9, 136.8,
137.8, 148.2, 150.8, 154.5, 156.6 ppm. HRMS (ESI-TOF, MeOH):
calcd. for [C21H18NO3]+ 332.1287; found 332.1269. C21H18BrNO3
(411.0470): calcd. C 61.18, H 4.40, N 3.40; found C 61.41, H 4.46,
N 3.33.
10-Fluoro-7-hydroxy-4-methylpyrido[2,1-a]isoquinolinylium Bromide
(1m): Pale brown solid (90 mg, 29%), m.p. Ͼ 300 °C (acetonitrile/
toluene). IR (KBr): ν = 2875, 1644, 1614, 1483, 1334, 1086,
˜
804 cm–1. 1H NMR (300 MHz, CD3OD): δ = 3.10 (s, 3 H, Me),
7.99 (td, J = 8.9, 2.3 Hz, 1 H), 8.13 (d, J = 7.6 Hz, 1 H), 8.27 (s, 1
H), 8.36 (app. t, J = 8.2 Hz, 1 H), 8.62 (dd, J = 8.9, 5.6 Hz, 1 H),
8.88 (dd, J = 10.2, 2.3 Hz, 1 H), 9.27 (d, J = 8.6 Hz, 1 H) ppm.
13C NMR (75 MHz, CD3OD): δ = 21.6 (1 C, Me), 109.3, 112.2 (d,
2JC,F = 26.1 Hz, 1 C), 122.9, 123.0, 123.6 (d, 2JC,F = 23.6 Hz, 1 C),
7-Hydroxy-9,10-dimethoxy-2-trifluoromethylpyrido[2,1-a]isoquinol-
inylium Bromide (1r): Pale brown solid (190 mg, 47 %), m.p. Ͼ
241 °C (dec.) (2-propanol). IR (KBr): ν = 3338, 3029, 1618, 1464,
˜
3
125.1, 127.3 (d, 3JC,F = 9.7 Hz), 127.7, 129.9 (d, JC,F = 11.2 Hz, 1
1
1308, 1177 cm–1. H NMR (300 MHz, CD3OD): δ = 4.16 (s, 3 H,
C), 136.9, 146.7, 152.0, 165.5 (d, 1JC,F = 251.5 Hz) ppm. MS (API-
3
OMe), 4.23 (s, 3 H, OMe), 7.86 (s, 1 H), 8.13 (dd, JH,H = 7.0,
ES, Pos): m/z
=
228.1 [C14H11FNO]+, [M]+. C14H11BrFNO
3
1.3 Hz, 1 H), 8.41 (s, 1 H), 8.51 (s, 1 H), 9.33 (d, JH,H = 7.0 Hz,
1 H), 9.53 (br. s, 1 H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ =
(307.0008): calcd. C 54.57, H 3.60, N 4.55; found C 54.27, H 3.66,
N 4.59.
56.0 (1 C, OMe), 56.6 (1 C, OMe), 101.2, 105.3, 112.9, 117.1 (q,
1
3JC,F = 3.1 Hz, 1 C), 120.6, 121.9 (q, JC,F = 273.9 Hz, 1 C, CF3),
4-Ethyl-10-fluoro-7-hydroxypyrido[2,1-a]isoquinolinylium Bromide
(1n): Pale brown solid (84 mg, 26%), m.p. 265–267 °C (acetonitrile/
3
2
123.3, 129.9 (q, JC,F = 3.1 Hz, 1 C), 131.8 (q, JC,F = 35.3 Hz, 1
C), 135.5, 137.5, 150.3, 152.1, 154.3 ppm. MS (API-ES, Pos): m/z
= 324.1 [C16H13F3NO3]+, [M]+. C16H13BrF3NO3 (403.0031): calcd.
C 47.55, H 3.24, N 3.47; found C 47.72, H 3.33, N 3.57.
toluene). IR (KBr): ν = 3357, 2886, 1610, 1481, 1333, 1088,
˜
3
801 cm–1. 1H NMR (300 MHz, CD3OD): δ = 1.63 (t, JH,H
=
3
7.3 Hz, 3 H, Me), 3.45 (q, JH,H = 7.3 Hz, 2 H, CH2), 7.99 (td, J
= 8.6, 2.3 Hz, 1 H), 8.13 (d, J = 7.4 Hz, 1 H), 8.40 (m, 2 H), 8.62
(dd, J = 8.8, 5.6 Hz, 1 H), 8.88 (dd, J = 10.5, 2.4 Hz, 1 H), 9.27
(d, J = 8.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 9.7
(1 C, CH3), 26.5 (1 C, CH2), 107.3, 110.7 (d, 2JC,F = 25.3 Hz, 1 C),
2,7-Dihydroxy-9,10-dimethoxypyrido[2,1-a]isoquinolinylium Bro-
mide (1s): Brown solid (152 mg, 43%), m.p. Ͼ 268 °C (dec.) (2-
propanol). IR (KBr): ν = 3391, 2971, 1647, 1610, 1477, 1284, 1246,
˜
1
1214, 1178 cm–1. H NMR (300 MHz, CD3OD): δ = 4.09 (s, 3 H,
2
3
121.3, 122.0 (d, JC,F = 24.6 Hz, 1 C), 123.5, 124.1, 125.6 (d, JC,F
OMe), 4.12 (s, 3 H, OMe), 7.39 (dd, JH,H = 7.5, 2.4 Hz, 1 H), 7.68
= 10.0 Hz, 1 C), 128.4 (d, 3JC,F = 9.9 Hz, 1 C), 135.4, 139.0, 149.3,
4
(s, 1 H), 7.92 (s, 1 H), 7.95 (s, 1 H), 8.17 (d, JH,H = 2.4 Hz, 1 H),
1
3
8.86 (d, JH,H = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CD3OD):
150.4, 163.8 (d, JC,F = 251.3 Hz, 1 C) ppm. MS (API-ES, Pos):
m/z = 242.2 [C15H13FNO]+, [M]+. C15H13BrFNO (321.0165): calcd.
δ = 56.9 (1 C, OMe), 57.1 (1 C, OMe), 103.4, 106.2, 106.3, 111.5,
115.2, 120.3, 124.6, 140.0, 141.9, 148.1, 153.6, 156.1, 165.2 ppm.
MS (API-ES, Pos): m/z = 272.3 [C15H14NO4]+, [M]+. C15H14BrNO4
(351.0106): calcd. C 51.16, H 4.01, N 3.98; found C 51.09, H 3.95,
N 4.13.
C 55.92, H 4.07, N 4.35; found C 56.10, H 4.02, N 4.49.
10-Fluoro-7-hydroxy-1,3-dimethylpyrido[2,1-a]isoquinolinylium Bro-
mide (1o): Pale brown solid (113 mg, 35%), m.p. Ͼ 300 °C (acetoni-
trile/toluene). IR (KBr): ν = 3414, 2841, 2543, 1653, 1610, 1481,
˜
1431, 1261, 1203, 860 cm–1. 1H NMR (300 MHz, CD3OD): δ =
2.65 (s, 3 H), 3.24 (s, 3 H), 7.94 (td, J = 8.4, 2.4 Hz, 1 H), 8.24 (br.
s, 1 H), 8.29 (s, 1 H), 8.62 (dd, J = 9.1, 6.1 Hz, 1 H), 8.79 (dd, J =
11.7, 2.0 Hz, 1 H), 9.11 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CD3OD): δ = 16.6 (1 C, Me), 24.4 (1 C, Me), 112.9, 114.2 (d, 2JC,F
7-Hydroxy-9,10-dimethoxy-1,3-dimethylpyrido[2,1-a]isoquinolin-
ylium Bromide (1t): Pale yellow solid (153 mg, 42%), m.p. Ͼ 260 °C
(dec.) (2-propanol). IR (KBr): ν = 3435, 3002, 1532, 1479, 1433,
˜
1287, 1203, 1169, 858 cm–1. 1H NMR (300 MHz, CD3OD): δ =
2.60 (s, 3 H, Me), 3.26 (s, 3 H, Me), 4.13 (s, 3 H, OMe), 4.14 (s, 3
H, OMe), 7.86 (s, 1 H), 8.06 (br. s, 1 H), 8.22 (s, 1 H), 8.39 (s, 1
H), 8.92 (br. s, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 17.8
(1 C, Me), 26.0 (1 C, Me), 56.9 (2 C, 2OMe), 103.3, 110.3, 113.7,
122.9, 125.7, 134.0, 135.4, 135.5, 135.9, 142.1, 150.6, 152.9,
155.1 ppm. HRMS (ESI-TOF, MeOH): calcd. for [C17H18NO3]+
284.1287; found 284.1304. C17H18BrNO3 (363.0470): calcd. C
56.06, H 4.98, N 3.85; found C 55.90, H 4.99, N 3.80.
2
= 26.8 Hz, 1 C), 120.8 (d, JC,F = 24.2 Hz, 1 C), 125.0, 125.5 (d,
3
3JC,F = 9.8 Hz, 1 C), 128.4 (d, JC,F = 10.0 Hz, 1 C), 134.9, 135.5,
1
136.2, 142.1, 142.2, 149.7, 162.8 (d, JC,F = 249.9 Hz, 1 C) ppm.
MS (API-ES, Pos): m/z
=
242.2 [C15H13FNO]+, [M]+.
C15H13BrFNO (321.0165): calcd. C 55.92, H 4.07, N 4.35; found
C 56.27, H 3.96, N 4.60.
7-Hydroxy-9,10-dimethoxypyrido[2,1-a]isoquinolinylium
Bromide
(1p): Pale brown solid (148 mg, 44%), m.p. Ͼ 254 °C (dec.) (2- 7-Hydroxy-9,10-dimethoxy-1,3,4-trimethylpyrido[2,1-a]isoquinol-
propanol). IR (KBr): ν = 3577, 3449, 2943, 1624, 1500, 1474, 1297, inylium Bromide (1u): Pale yellow solid (178 mg, 47%), m.p. Ͼ
˜
1264, 1218, 1183 cm–1. H NMR (300 MHz, CD3OD): δ = 4.13 (s, 270 °C (dec.) (2-propanol). IR (KBr): ν = 3435, 3118, 2769, 2578,
1
˜
3
1
3 H, OMe), 4.17 (s, 3 H, OMe), 7.78 (s, 1 H), 7.90 (app. t, JH,H
=
1640, 1488, 1288, 1211 cm–1. H NMR (300 MHz, [D6]DMSO): δ
3
6.8 Hz, 1 H), 8.25 (m, 3 H), 9.10 (d, JH,H = 6.6 Hz, 1 H), 9.18 (d,
3JH,H = 8.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 55.6
(1 C, OMe), 55.9 (1 C, OMe), 101.7, 104.7, 111.7, 120.5, 122.2,
122.4, 123.6, 134.5, 136.2, 137.6, 149.8, 153.1, 155.2 ppm. HRMS
(ESI-TOF, MeOH): calcd. for [C15H14NO3]+ 256.0974; found
= 2.60 (s, 3 H, Me), 2.82 (s, 3 H, Me), 3.16 (s, 3 H, Me), 4.05 (s, 3
H, OMe), 4.06 (s, 3 H, OMe), 7.71 (br. s, 1 H), 8.15 (br. s, 1 H),
8.27 (m, 2 H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 17.1 (1
C, Me), 19.1 (1 C, Me), 24.6 (1 C, Me), 55.6 (1 C, OMe), 55.7 (1
C, OMe), 100.9, 108.5, 109.2, 120.8, 122.0, 130.7, 131.2, 136.0,
626
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 619–628

Radical Intramolecular Arylation of Pyridinium Salts
139.9, 148.0, 150.0, 152.3, 166.3 ppm. MS (API-ES, Pos): m/z =
Supporting Information (see also the footnote on the first page of
298.0 [C18H20NO3]+, [M]+. C18H20BrNO3 (377.0627): calcd. C this article): Selected 1H and 13C NMR spectra of new compounds.
51.16, H 5.33, N 3.70; found C 51.02, H 5.31, N 3.78.
6-Hydroxy-4b-azoniachrysene Bromide (1v): Yellow solid (155 mg,
Acknowledgments
47%), m.p. Ͼ 246 °C (dec.) (acetonitrile). IR (KBr): ν = 2918, 1601,
˜
1529, 1459, 1362, 761 cm–1. 1H NMR (300 MHz, CD3OD): δ =
3
8.08 (app. t, JH,H = 7.8 Hz, 1 H), 8.23 (m, 3 H), 8.41 (dd, JH,H
=
The authors acknowledge support from the Ministerio de Ciencia
e Innovación (MICINN) (project CTQ2008-05027/BQU2), the
Instituto de Salud Carlos III (Red de Investigación Renal,
REDinREN, RD06/0016/0016) and a grant from SERVIER S.A.
(to R. R. C.).
3
7.9, 1.5 Hz, 1 H), 8.60 (dd, JH,H = 8.9, 1.5 Hz, 1 H), 8.80 (d, JH,H
= 9.4 Hz, 1 H), 8.88 (d, JH,H = 8.8 Hz, 1 H), 9.20 (m, 3 H) ppm.
3
13C NMR (50 MHz, CD3OD): δ = 110.5, 119.0, 119.3, 123.8, 127.7,
127.8, 128.9, 129.7, 131.3, 131.8, 133.0, 134.8, 135.6, 136.0, 137.6,
140.7, 152.4 ppm. HRMS (ESI-TOF, MeOH): calcd. for
[C17H12NO]+ 246.0919; found 246.1025. C17H12BrNO (325.9919):
calcd. C 62.60, H 3.71, N 4.29; found C 62.55, H 3.76, N 4.57.
[1] a) E. Schraufstaetter, Angew. Chem. 1962, 74, 874–875; b) P. A.
Duke, A. Fozard, G. Jones, J. Org. Chem. 1965, 30, 526–528;
c) E. I. Kostik, A. Abiko, A. Oku, J. Org. Chem. 2001, 66,
1638–1646.
[2] a) V. Carelli, F. Liberatore, G. Casini, Ann. Chim. (Rome)
1967, 57, 269–278; b) W. M. Golebiewski, J. T. Wrobel, Bull.
Pol. Acad. Sci. 1990, 38, 17–27.
[3] a) Y. Matsuda, H. Gotou, M. Yamashita, K. Takahashi, S. Ide,
K. Furuno, K. Torisu, T. Itou, C. Motokawa, Heterocycles
1992, 34, 2277–2280; b) Y. Matsuda, S. Kohra, K. Katou, T.
Itou, T. Uemura, Heterocycles 1998, 48, 2573–2579.
6-Hydroxy-8,9-dimethoxy-4b-azoniachrysene Bromide (1w): Bright
yellow solid (166 mg, 43%), m.p. Ͼ 247 °C (dec.) (2-propanol). IR
(KBr): ν = 2832, 1606, 1497, 1302, 1224 cm–1. 1H NMR (300 MHz,
˜
CD3OD): δ = 4.11 (s, 3 H, OMe), 4.17 (s, 3 H, OMe), 7.68 (app. t,
3
3JH,H = 7.6 Hz, 1 H), 7.69 (d, JH,H = 7.6 Hz, 1 H), 8.14 (m, 2 H),
3
3
8.24 (d, JH,H = 7.3 Hz, 1 H), 8.50 (d, JH,H = 9.1 Hz, 1 H), 8.66
(d, JH,H = 8.8 Hz, 1 H), 8.95 (m, 2 H) ppm. 13C NMR (75 MHz,
3
CD3OD): δ = 57.2 (1 C, OMe), 57.3 (1 C, OMe), 102.7, 106.8,
118.5, 119.4, 123.1, 126.7, 128.3, 130.8, 131.7, 134.2, 135.8, 138.5,
[4] a) C. K. Bradsher, N. L. Dutta, J. Am. Chem. Soc. 1960, 82,
1145–1147; b) S. Saraf, Heterocycles 1981, 16, 803–841; c) G.
Jones, Adv. Heterocycl. Chem. 1982, 31, 1–62; d) Y. Tominaga,
Sci. Synth. 2004, 17, 1025–1079; e) H. Ihmels, Sci. Synth. 2005,
15, 907–945; f) A. Nuñez, A. M. Cuadro, J. Alvarez-Builla, J. J.
Vaquero, Org. Lett. 2007, 9, 2977–2980; g) E. Beausoleil, C.
Chauvignac, T. Taverne, S. Lacombe, L. Pognante, B. Leblond,
D. Pallares, C. De Oliveira, F. Bachelot, R. Carton, H. Peillon,
S. Coutadeur, V. Picard, N. Lambeng, L. Desire, F.
Schweighoffer, Bioorg. Med. Chem. Lett. 2009, 19, 5594–5598;
h) Y. X. Wang, Y. P. Wang, H. Zhang, W. J. Kong, Y. H. Li, F.
Liu, R. M. Gao, T. Liu, J. D. Jiang, D. Q. Song, Bioorg. Med.
Chem. Lett. 2009, 19, 6004–6008.
[5] W. Zhang, G. Pugh, Tetrahedron 2003, 60, 3009–3018.
[6] a) J. A. Murphy, M. S. Sherburn, Tetrahedron Lett. 1990, 31,
1625–1628; b) J. A. Murphy, M. S. Sherburn, Tetrahedron Lett.
1990, 31, 3495–3496.
[7] Y. T. Park, N. W. Song, Y. H. Kim, C. G. Hwang, S. K. Kim,
D. Kim, J. Am. Chem. Soc. 1996, 118, 11399–11405.
[8] A. P. Dobbs, K. Jones, K. T. Veal, Tetrahedron Lett. 1997, 38,
5383–5386.
[9] a) V. Martínez-Barrasa, A. García de Viedma, C. Burgos, J. Al-
varez-Builla, Org. Lett. 2000, 2, 3933–3935; b) A. Núñez, A.
Sánchez, C. Burgos, J. Alvarez-Builla, Tetrahedron 2004, 60,
6217–6224; c) A. Sánchez, A. Núñez, C. Burgos, J. Alvarez-
Builla, Tetrahedron 2004, 60, 11843–11850; d) A. Sánchez, A.
Núñez, C. Burgos, J. Alvarez-Builla, Tetrahedron Lett. 2006,
47, 8343–8346; e) A. Núñez, A. Sánchez, C. Burgos, J. Alvarez-
Builla, Tetrahedron 2007, 63, 6774–6783.
[10] a) A. Núñez, A. García de Viedma, V. Martínez-Barrasa, C.
Burgos, J. Alvarez-Builla, Synlett 2002, 1093–1096; b) V. Abet,
A. Núñez, F. Mendicuti, C. Burgos, J. Alvarez-Builla, J. Org.
Chem. 2008, 73, 8800–8807.
[11] For some examples of homolytic aromatic substitution, see: a)
T. C. T. Ho, K. Jones, Tetrahedron 1997, 53, 8287–8294; b)
A. K. Ganguly, C. H. Wang, M. David, P. Bartner, T. M. Chan,
Tetrahedron Lett. 2002, 43, 6865–6868; c) W. Zhang, G. Pugh,
Tetrahedron 2003, 59, 3009–3018; d) H. Ohno, H. Iwasaki, T.
Eguchi, T. Tanaka, Chem. Commun. 2004, 2228–2229; e) W. R.
Bowman, J. M. D. Storey, Chem. Soc. Rev. 2007, 36, 1803–
1822.
[12] a) D. C. Harrowven, M. I. T. Nunn, Tetrahedron Lett. 1998, 39,
5875–5876; b) D. C. Harrowven, M. I. T. Nunn, N. J. Blumire,
D. R. Fenwick, Tetrahedron Lett. 2000, 41, 6681–6683; c) D. C.
Harrowven, M. I. T. Nunn, N. J. Blumire, D. R. Fenwick, Tet-
151.4, 154.9, 157.7 ppm. MS (API-ES, Pos): m/z
=
306.1[C19H16NO3]+, [M]+. C19H16BrNO3 (386.24): calcd. C 59.08,
H 4.18, N 3.63; found C 58.88, H 4.21, N 3.75.
5-Hydroxy-8-methylisoquino[1,2-a]isoquinolinylium Bromide (1x):
Bright yellow solid (171 mg, 50%), m.p. Ͼ 270 °C (dec.) (acetoni-
trile/2-propanol). IR (KBr): ν = 3326, 2845, 2560, 2254, 1657, 1598,
˜
1526, 1448, 1413, 1348, 1082, 759 cm–1. 1H NMR (300 MHz,
3
CD3OD): δ = 3.09 (s, 3 H, Me), 7.99 (app. t, JH,H = 7.7 Hz, 1 H),
8.09 (m, 2 H), 8.21 (m, 2 H), 8.31 (s, 1 H), 8.42 (s, 1 H), 8.59 (d,
3
3
3JH,H = 8.2 Hz, 1 H), 8.93 (d, JH,H = 8.2 Hz, 1 H), 9.06 (d, JH,H
= 8.5 Hz, 1 H) ppm. 13C NMR (50 MHz, CD3OD): δ = 21.1 (1 C,
Me), 111.2, 123.2, 125.0, 125.6, 127.2, 128.2, 129.9, 131.1, 131.2,
132.1, 132.4, 134.1, 134.5, 134.9, 138.4, 141.9, 151.6 ppm. MS
(API-ES, Pos): m/z = 260.2 [C18H14NO]+, [M]+. C18H14BrNO
(340.0075): calcd. C 63.55, H 4.15, N 4.12; found C 63.71, H 4.18,
N 4.07.
10-Hydroxy-8b-azoniabenzo[g]chrysene Bromide (1y): Bright yellow
solid (169 mg, 45%), m.p. Ͼ 281 °C (dec.) (acetonitrile/2-propa-
nol). IR (KBr): ν = 2934, 1623, 1598, 1458, 1404, 1364, 754 cm–1.
˜
1H NMR (300 MHz, CD3OD): δ = 8.11 (m, 6 H), 8.29 (app. t,
3
3JH,H = 7.9 Hz, 1 H), 8.69 (m, 2 H), 8.88 (d, JH,H = 8.8 Hz, 1 H),
9.04 (m, 3 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 120.2, 123.4,
124.6, 124.7, 126.0, 126.3, 127.7, 130.7, 131.6, 131.7, 132.1, 132.3,
132.8, 133.3, 133.7, 133.8, 134.8, 135.9, 144.1, 152.4 ppm. HRMS
(ESI-TOF, MeOH): calcd. for [C21H14NO]+ 296.1075; found
296.1076. C21H14BrNO (376.0075): calcd. C 67.04, H 3.75, N 3.72;
found C 67.17, H 3.82, N 3.97.
8-Hydroxy-6-aza-6a-azoniabenzo[c]phenanthrene Bromide (1z): Pale
brown solid (88 mg, 27%), m.p. 226–229 °C (2-propanol). IR
(KBr): ν = 3417, 3010, 2810, 1721, 1428, 1346, 761 cm–1. 1H NMR
˜
(300 MHz, CD3OD): δ = 7.63 (m, 2 H), 7.88 (dd, JH,H = 7.5,
1.3 Hz, 1 H), 8.02 (dd, JH,H = 7.5, 1.7 Hz, 1 H), 8.52 (td, JH,H
=
3
7.2, 1.6 Hz, 1 H), 8.70 (m, 2 H), 8.77 (d, JH,H = 8.2 Hz, 1 H),
10.04 (s, 1 H), 10.61 (s, 1 H) ppm. 13C NMR (50 MHz, CD3OD):
δ = 121.1, 129.1, 129.2, 129.5, 129.7, 130.6, 131.7, 132.0, 133.0,
135.2, 136.0, 137.1, 137.8, 141.4, 154.1, 156.2 ppm. HRMS (ESI-
TOF, MeOH): calcd. for [C16H11N2O]+ 247.0871; found 247.0868.
C16H11BrN2O (326.0055): calcd. C 58.74, H 3.39, N 8.56; found C
58.66, H 3.45, N 8.89.
Eur. J. Org. Chem. 2011, 619–628
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
627

R. R. Castillo, C. Burgos, J. J. Vaquero, J. Alvarez-Builla
FULL PAPER
rahedron 2001, 57, 4447–4454; d) D. C. Harrowven, B. J. Sut-
ton, Prog. Heterocycl. Chem. 2004, 16, 27–53.
[13] A. Ryokawa, H. Togo, Tetrahedron 2001, 57, 5915–5921.
[14] a) E. Winterfeldt, Chem. Ber. 1964, 97, 2463–2468; b) E. Chro-
bak, A. Maslankiewicz, Heterocycles 2004, 63, 2329–2340.
[15] F. Minisci, F. Fontana, G. Morini, M. Serravalle, C. Giordano,
J. Org. Chem. 1987, 52, 730–736.
[16] a) G. A. Russell, P. Chen, B. H. Kim, R. Rajaratnam, J. Am.
Chem. Soc. 1997, 119, 8795–8801; b) C. Wang, G. A. Russell,
W. S. Trahanovsky, J. Org. Chem. 1998, 63, 9956–9959.
[17] An additional experiment was carried out on 6a using acetic
acid as the solvent. Surprisingly, we observed a total conversion
of starting material and 71% of cyclized product was detected
by HPLC-MS [Agilent 1100, Luna C-18, 10 cmϫ4.6 mm,
3 μm, mobile phase water/0.1% formic acid,(A)/MeOH/0.1%
formic acid (B) gradient: t0 = 90% (A) to t = 20 min, 100%
(B)]. Further experiments are in progress to test the reproducib-
ility and applicability of this process as a general method for
the cyclization of (bromophenyl)oxoethylpyridinium bromides
6. Improvement of the solubility of phenacylpyridinium salt 6a
could play a role in the observed effect.
[21]
[22]
L. Labanauskas, A. Brukstus, E. Udrenaite, V. Bucinskaite, I.
Susvilo, G. Urbelis, Farmaco 2005, 60, 203–207.
a) M. B. Young, J. C. Barrow, K. L. Glass, G. F. Lundell, C. L.
Newton, J. M. Pellicore, K. E. Rittle, H. G. Selnick, K. J.
Stauffer, J. P. Vacca, P. D. Williams, D. Bohn, F. C. Clayton,
J. J. Cook, J. A. Krueger, L. C. Kuo, S. D. Lewis, B. J. Lucas,
D. R. McMasters, C. Miller-Stein, B. L. Pietrak, A. A. Wallace,
R. B. White, B. Wong, Y. Yan, P. G. Nantermet, J. Med. Chem.
2004, 47, 2995–3008; b) S. Udd, R. Jokela, R. Franzen, J. Tois,
Tetrahedron Lett. 2010, 51, 1030–1033.
a) C. Zhang, J. Dumas, G. H. Ladouceur, Q. Zhao, M. F. Hen-
temann, S. K. Verma, Q. Zhu, R. C. Lavoie, J. Fan, B. Phillips,
PCT Int. Appl. 2005, WO 2005014566-A1-20050217; b) O. We-
ber, V. Voehringer, H. G. Lerchen, F. T. Hafner, J. Keldenich,
K. H. Schlemmer, U. Krenz, B. Riedl, PCT Int. Appl. 2008,
WO 2008025509-A1-20080306.
[23]
[24] a) F. Kröhnke, Ber. Dtsch. Chem. Ges. 1937, 70, 864–878; b)
A. V. Malkov, F. Friscourt, M. Bell, M. E. Swarbrick, P. Ko-
covsky, J. Org. Chem. 2008, 73, 3996–4003.
[25] G. Rosseels, M. Peiren, F. Henaux, M. Prost, M. Descamps, C.
Tornay, J. Richard, J. Bauthier, M. Colot, M. De Claviere, Ann.
Pharm. Fr. 1982, 40, 241–249.
[18] Y. Y. Han, Z. J. Wu, X. M. Zhang, W. C. Yuan, Tetrahedron
Lett. 2010, 51, 2023–2028.
[19] J. W. Baker, J. Chem. Soc. 1932, 1148–1157.
[20] C. Casagrande, A. Invernizzi, R. Ferrini, G. Miragoli, Farmaco
1971, 26, 1059–1073.
Received: July 28, 2010
Published Online: December 6, 2010
628
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 619–628