An efficient entry to pyrrolo[1,2-b]isoquinolines and related systems through Parham cyclisation

Article abstract of DOI:10.1016/j.tet.2004.10.105

Aryllithiums generated by lithium-iodine exchange undergo intramolecular cyclisation to give pyrrolo[1,2-b]isoquinolines, in high yields. The best results were obtained when Weinreb or morpholine amides were used as internal electrophiles. The procedure h

Full text of DOI:10.1016/j.tet.2004.10.105

Tetrahedron 61 (2005) 3311–3324
An efficient entry to pyrrolo[1,2-b]isoquinolines and related
systems through Parham cyclisation
*
Javier Ruiz, Ainhoa Ardeo, Roberto Ignacio, Nuria Sotomayor and Esther Lete
´ ´ ´ ´
Departamento de Quımica Organica II, Facultad de Ciencia y Tecnologıa, Universidad del Paıs Vasco/Euskal Herriko Unibertsitatea,
Apdo. 644. 48080 Bilbao, Spain
Received 5 August 2004; revised 29 September 2004; accepted 15 October 2004
Available online 24 November 2004
Abstract—Aryllithiums generated by lithium–iodine exchange undergo intramolecular cyclisation to give pyrrolo[1,2-b]isoquinolines, in
high yields. The best results were obtained when Weinreb or morpholine amides were used as internal electrophiles. The procedure has been
extended to the preparation of seven and eight membered rings, opening a route to benzazepine and benzazocine skeletons.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
than the carboxylates in Parham-type cycliacylations.6 For
instance, Avendan˜o7 has applied this protocol to the
synthesis of 1,8-diazanthracene-9,10-diones using a tandem
directed ortho-metalation/metal–halogen exchange reac-
tions. Various amides can be used for these reactions and,
in some cases, it has been reported that there is an influence
of the nature of the susbstituents at nitrogen in the course of
the cyclisation reaction. Thus, Quallich8 has prepared
azatetralones starting from 3-bromopyridines with a N,N-
dialkylaminocarbonylpropyl substituent at C-2. Although
three different amides (dimethyl, diisopropyl, and pyrroli-
dine) were tested as substrates for this carbanionic ring
annelation, best results were obtained with the N,N-
dimethyl derivative. However, when Wu et al.9 applied a
similar Parham cyclisation protocol to the synthesis of
dibenzocycloheptenone derivatives, they found no signifi-
cant influence of the nitrogen substitution pattern in the
cyclisation yields.
Aryl and heteroaryllithium compounds1 are interesting
building blocks in synthetic organic chemistry because by
reaction with carbon electrophiles they produce, together
with the formation of a carbon–carbon bond, the transfer-
ence of functionality to the electrophilic reagent, so
polyfunctionalised molecules can be prepared in one step.
Lithium–halogen exchange, though mechanistically con-
troversial,2 is a particularly useful tactic for the metalation
of aromatic substrates, because metal–halogen exchange
can effectively compete with the organolithium reaction
with internal electrophiles.3 Once generated, the aryl-
lithiums may react with internal or external electrophiles
and give rise to cyclisation reactions.
The intramolecular cyclisations that employ aryllithiums
generated by lithium–halogen exchange are known as
Parham cyclisations. Thus, the aromatic metalation–cycli-
sation sequence has become a valuable protocol for the
regiospecific construction of carbocyclic and heterocyclic
systems.4 When the internal electrophile is a carboxylate,
this anionic cyclisation could be considered as an anionic
Friedel–Crafts equivalent, with the advantage that it lacks
the electronic requirements of the classical reaction. The
complementary character of the anionic and classical
cyclisations is exemplified by the synthesis of azafluorenone
alkaloids.5 Acid derivatives, such as amides and carbamates
constitute even more effectively used internal electrophiles
On the other hand, Weinreb10 amides have been widely used
in synthesis, although their use in Parham cyclisations is
scarce. Thus, aryl and heteroaryllithium compounds have
been generated in the presence of this group to give access
to benzocyclobutenones,11 thieno[2,3-b]thiophenes,12 or
methylideneindanones.13 Weinreb amides have also been
successfully used as internal electrophiles in cyclisation
reactions of organolithiums derived from alkyl iodides,
accessing cyclic ketones,14 or vinyl iodides, in the synthesis
of (K)-Brunsvigine,15 or the hexahydrobenzofuran subunit
of Avermeticin.16
Keywords: Lithiation; Lithium–halogen exchange; Parham cyclisation;
Pyrrolo[1,2-b]isoquinoline.
* Corresponding author. Tel.: C34 946012576; fax: C34 946012748;
e-mail: qopleexe@lg.ehu.es
In connection with our interest in aromatic lithiation,17 we
decided to develop an anionic cyclisation approach toward
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.105

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J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
the construction of the pyrrolo[1,2-b]isoquinolone core
present in some natural products such as the lycorine class
of Amaryllidaceae alkaloids18 and the phenanthroindolizi-
dine alkaloids.19 In the planned synthetic strategy, an
aryllithium would be generated from a N-(o-halobenzyl)-
pyrrole-2-carboxamide, that is expected to undergo a 6-exo-
trig cyclisation onto the amide carbonyl of the pyrrole ring
to provide the target heterocycle. A key feature of this
synthetic approach is the ability of the amide moiety to
intercept the aryllithium in an intramolecular fashion.
Therefore, in order to study the influence of the nature of
the substituents at the amide nitrogen atom on Parham-type
cyclisations, this metalation–cyclisation sequence would be
tested using different types of amides (N,N-dialkyl, Weinreb
amides and morpholine amides) as internal electrophiles. It
should be pointed out that, although morpholine amides are
expected to be good electrophiles, and have been used in
acylation reaction with organometallic reagents,20 they have
not been used in Parham-type cyclisations. However, the
low cost of the morpholine, compared to the MeONH-
Me$HCl that is needed to make the Weinreb amides, led us
to test the morpholine amides as internal electrophiles.
Herein, we provide the full account of our investigations in
this area,21 including the extension of this strategy to the
construction of seven and eight membered rings.
2. Results
2.1. Synthesis of N-benzylpyrroles
The study started with the synthesis of the substrates 5–7
with different substituents at the aromatic ring to prove the
generality of the approach. Thus, N-(o-iodobenzyl)pyrroles
were prepared by alkylation of the corresponding pyrrole-2-
carboxamide 4a–c under standard conditions (Scheme 1,
Table 1). Iodobenzyl bromides 3a–g were obtained from the
corresponding benzylic alcohols 1 in two steps. Aromatic
iodination of benzylic alcohols 1b–g with I2/CF3CO2Ag in
CHCl3 afforded alcohols 2b–g in good yields (64–94%). In
all cases the reaction was completely regioselective, except
in e, where a minor amount of the 5-iodo regioisomer was
obtained (see Section 3). Subsequent treatment with PBr3
for cases a–f, or with HBr for g afforded bromides 3a–g
(86–99%).
2.2. Parham cyclisation of N-benzylpyrroles
We started studying the N,N-diethylcarbamoyl group as an
internal electrophile. The metalation–cyclisation sequence
was carried out under several conditions, using t-BuLi
(2.2 equiv). Cyclisation conditions had to be optimised
for each substrate 5a–g, and minor amounts of deiodinated
N-benzylpyrroles 9a–g were always isolated together with
the pyrrolisoquinolines 8. For instance, when benzylpyrrole
5d was treated with t-BuLi (2.2 equiv) at K78 8C for 3 h,
and the reaction was quenched at 0 8C, pyrrolosoquinoline
8d was obtained in 49% yield, together with 9d (24%)
(Fig. 1). However, if the reaction mixture was allowed to
reach rt, and stirred for 3 h, the pyrroloisoquinoline 8d was
obtained in 79% yield (Table 2, entry 4). Thus, iodine–
lithium exchange took place efficiently at K78 8C, but
higher temperature was required for cyclisation. As shown
in Table 2, some of the substrates required even longer
periods at room temperature (entry 6), or the use of n-BuLi
as metalating agent (entry 2). Thus, when 5f or 5b were
treated with t-BuLi under the standard conditions (Method
A), the corresponding deiodinated benzylpyrroles 9f or 9b
were obtained (39 and 33% respectively). Under all
conditions tested, no cyclisation product was obtained
from 5g which, under standard conditions gave only
deiodinated product 9g (81%, entry 7). In general, only
moderate yields of pyrroloisoquinolines were obtained
when the aromatic ring is activated by donor groups.
Although in related Parham-type cyclisations no influence
of the aromatic ring substitution pattern has been
observed,22 it seems that, once the iodine–lithium exchange
Scheme 1. Synthesis of N-benzylpyrroles 5–7. Reagents: (a) I2, CF3CO2Ag,
CHCl3, rt; (b) PBr3, rt or HBr (45%), 0 8C; (c) KOH, DMSO, rt.
Table 1. Synthesis of benzylpyrroles 5, 6, and 7 by alkylation of 4
Entry
R5ZNEt2
R5ZN(OMe)Me
R5Z
Product
Yield (%)
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
60
83
94
73
25
84
56
6a
6b
6c
6d
6e
6f
90
78
83
95
61
77
73
7a
7b
7c
7d
7e
7f
63
98
86
93
50
68
40
5g
6g
7g

J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
3313
Scheme 2. Parham cyclisation of benzylpyrroles 5–7.
Table 2. Synthesis of pyrrolo[1,2-b]isoquinolines
Entry
Product
R5ZNEt2
R5ZN(OMe)Me
R5Z
Method Aa,
yield (%)
Method Aa,
yield (%)
Method Aa,
yield (%)
Method Bb,
yield (%)
Method Bb,
yield (%)
1
2
3
8a
8b
8c
28c
10c
54
83
87
80
69
73
63
60
77
60
81
98
77
4
5
8d
8e
79
40
70
24
86
62
60
40
88
76
6
7
8f
34d
62
15
73
68
60
—
63
59
e
8g
a Method A: t-BuLi (2.2 equiv), K78 8C, 3 h; /rt, 4 h.
b Method B: t-BuLi (2.2 equiv), K78 8C, 3 h.
c n-BuLi (3 equiv), K78 8C, 3 h; /rt, 4 h.
d t-BuLi (2.2 equiv), K78 8C, 3 h; /rt, 16 h.
e 81% of deiodinated benzylpyrrole 9g was obtained.
has occurred, the more reactive aryllithium compounds lead
to better yields of pyrroloisoquinolines 8 (Scheme 2).
reactions were quenched at K78 8C (Method B), yields of
pyrroloisoquinolines 8 were consistently improved. Most
significant is the improvement of the yield of pyrroloiso-
quinolines 8e (24% vs. 62% from 6e and 40% vs. 76% from
7e) and 8g (15% vs. 68% from 6g and 0% vs. 59% from 7g)
(Table 2, entries 5 and 7). In these cases, the poor results
obtained when the reactions are quenched at room
temperature might be due to an equilibration of the
intermediate organolithium prior to cyclisation. Thus, as
shown in Table 2, in all cases the use of Weinreb amides or
morpholine amides as internal electrophiles clearly
improved the results obtained with diethyl amides. The
most significant results would be the synthesis of pyrrolo-
isoquinolines 8a, 8b, or 8g.
We next focused our attention on the metalation–cyclisation
sequence using Weinreb amides 6 and morpholine amides 7.
As shown in Table 2, both types of amides gave moderate to
good yields of pyrroloisoquinolines 8 under Method A
conditions, except when the aromatic ring bears methoxy
groups on C-6 or C-3 (entries 5 and 7). However, when the
Amides are generally useful electrophiles in Parham
cyclisations due to a complex induced proximity effect
(CIPE).23,24 Thus, lithium–iodine exchange could be
favoured first by coordination of the organolithium to the
Figure 1. Deiodinated N-benzylpyrroles 9a–g.

3314
J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
Table 3. Synthesis of 15 and 16
Substrate
Methoda
Product
Yield, %
13a
14a
13b
14b
B
B
B
B
15
15
16
16
59
58
55
57
a Method B: t-BuLi (2.2 equiv), K78 8C, 3 h.
Figure 2.
amide group, and second, by stabilisation of the resulting
aryllithium. Although there is no significant difference in
the efficiency of Weinreb amides and morpholine amides as
internal electrophiles, the better behaviour of both com-
pared to N,N-diethyl amides could be attributed to the extra
stabilisation of the intermediate generated after cyclisation
by formation of an internal chelate, as depicted in Figure 2.
using 2.2 equiv of t-BuLi at K78 8C. As shown in Table 3,
moderate to good yields of the pyrrolo[1,2-a]benzo[d]-
azepine-11-one 15 and pyrrolo[1,2-a]benzo[d]azozin-12-
one 16 were obtained when the reaction was quenched at
low temperature.
In summary, it has been shown that N-(o-iodobenzyl)-
pyrrole-2-carboxamides tolerate lithium–iodine exchange
reaction conditions, allowing the efficient synthesis of the
pyrrolo[1,2-b]isoquinoline nucleus. The N-methoxy-N-
methyl and morpholine amides behave as excellent internal
electrophiles, improving the results obtained with N,N-
diethyl amides. This procedure has also been extended to the
construction of fused seven and eight membered rings,
opening also new routes to other heterocyclic systems
(pyrrolo[1,2-a]benzazepines and pyrrolo[1,2-a]benzo-
azocines) with potential pharmacological properties that
could compete with previously reported strategies.27
2.3. Parham cyclisation of N-phenethyl- and N-
phenylpropylpyrroles
In view of the excellent results obtained in the formation of
pyrrolosoquinoline ring system with Weinreb amides or
morpholine amides, we decided to investigate the feasibility
of using this type of Parham cyclisation to construct a seven
or an eight-membered ring, opening a new access to the
pyrrolobenzoazepine and pyrrolobenzoazocine skeletons.
The pyrrolobenzoazepine core is present in Cephalotaxus
alkaloids,25 and some pyrrolobenzoazepines have muscle
relaxant, antihypertensive or antipsychotic properties.26
Thus, the required pyrrole-2-carboxamides 13 and 14 and
were obtained from 3,4-dimethoxyphenethyl alcohol 10a
and 3,4-dimethoxyphenylpropan-1-ol 10b in three steps, as
described in Scheme 3. Parham cyclisation was carried out
3. Experimental
3.1. Iodination reactions. General procedure
A solution of I2 (250 mg, 1 mmol) in dry CHCl3 (30 mL)
was added over a suspension of CF3COOAg (220 mg,
1 mmol) and alcohols 1b–g, or 10a,b (1 mmol) in CHCl3
(5 mL). The reaction mixture was stirred at rt during 30 min,
the resulting AgI precipitate was filtered, and the resulting
solution was washed with saturated Na2S2O3. Evaporation
of the solvent afforded iodinated alcohols 2b–g, or 11a,b,
which were crystallised from Et2O.
3.1.1. 2-Iodo-4,5-dimethylbenzyl alcohol (2b). According
to the general procedure, alcohol 1b (136 mg, 1 mmol) was
treated with I2 (250 mg, 1 mmol) and CF3COOAg (220 mg,
1 mmol) in CHCl3 (30 mL). After work-up, alcohol 2b was
recrystallised from Et2O (183 mg, 70%): mp (Et2O) 110–
1
112 8C; IR (KBr) 3260 cmK1; H NMR (CDCl3) 2.20 (s,
3H), 2.21 (s, 3H), 4.58 (s, 2H), 7.17 (s, 1H), 7.57 (s, 1H); 13C
NMR (CDCl3) 18.9, 19.3, 68.9, 93.8, 129.8, 137.1, 138.2,
139.7, 139.8. MS (EI) m/z (rel intensity) 262 (MC, 78), 245
(11), 135 (30), 133 (21), 107 (84), 106 (31), 105 (37), 103
(17), 92 (33), 91 (100), 85 (28), 83 (42), 79 (32), 78 (14), 77
(35), 65 (20), 63 (17), 53 (11), 51 (23). Anal. Calcd for
C9H11IO: C, 41.24; H, 4.23. Found: C, 41.59; H, 3.94.
3.1.2. 2-Iodo-5-methoxybenzyl alcohol (2c).28 According
to the general procedure, alcohol 1c (136 mg, 1 mmol) was
treated with I2 (250 mg, 1 mmol) and CF3COOAg (220 mg,
1 mmol) in CHCl3 (30 mL). After work-up, alcohol 2c was
recrystallised from Et2O (167 mg, 64%): mp (Et2O) 64–
65 8C; IR (KBr) 3260 cmK1; 1H NMR (CDCl3) 3.10 (s, 1H),
3.75 (s, 3H), 4.54 (s, 2H), 6.54 (dd, JZ8.7, 2.8 Hz, 1H),
Scheme 3. Parham cyclisation of N-phenethyl and N-phenylpropylpyrroles.
Reagents: (a) I2, CF3CO2Ag, CHCl3, rt; (b) TsCl or MsCl, Et3N, CH2Cl2,
0 8C; (c) KOH, DMSO, rt; (d) t-BuLi, K78 8C, 3 h.

J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
3315
7.01 (d, JZ2.8 Hz, 1H), 7.60 (d, JZ8.7 Hz, 1H); 13C NMR
(CDCl3) 55.2, 68.7, 85.1, 113.8, 115.0, 139.3, 143.4, 159.9.
The rest of the spectroscopic and physical data are
consistent with those described in the literature.28
3.1.7. 2-(2-Iodo-4,5-dimethoxyphenyl)ethanol (11a).32
According to the general procedure, alcohol 10a (1 g,
6 mmol) was treated with I2 (1.5 g, 6 mmol) and CF3-
COOAg (1.33 g, 6 mmol) in CHCl3 (100 mL). After work-
up, alcohol 11a was recrystallised from Et2O (1.8 g, 99%):
mp (Et2O) 53–54 8C; IR (neat) 3580 cmK1 1H NMR
;
3.1.3. 2-Iodo-4,5-dimethoxybenzyl alcohol (2d).29
According to the general procedure, alcohol 1d (168 mg,
1 mmol) was treated with I2 (250 mg, 1 mmol) and
CF3COOAg (220 mg, 1 mmol) in CHCl3 (30 mL). After
work-up, alcohol 2d was recrystallised from Et2O (188 mg,
64%): mp (Et2O) 83–85 8C; IR (KBr) 3270 cmK1; 1H NMR
(CDCl3) 2.40 (s, 1H), 3.84 (s, 6H), 4.56 (s, 2H), 6.97 (s, 1H),
7.18 (s, 1H); 13C NMR (CDCl3) 55.8, 56.1, 68.9, 85.2,
111.4, 121.3, 135.1, 148.7, 149.3. The rest of the spectro-
scopic and physical data are consistent with those described
in the literature.29
(CDCl3) 2.27 (s, 1H), 2.87 (t, JZ6.7 Hz, 2H,), 3.75 (t, JZ
6.7 Hz, 2H), 3.78(s, 3H), 3.79 (s, 3H), 6.73 (s, 1H), 7.15 (s,
1H); 13C NMR (CDCl3) 43.1, 55,8, 56.0, 62.2, 88.1, 112.9,
121.5, 133.3, 147.9, 149.0. The rest of the spectroscopic and
physical data are consistent with those described in the
literature.32
3.1.8. 3-(2-Iodo-4,5-dimethoxyphenyl)propan-1-ol (11b).
According to the general procedure, alcohol 10b (6.3 g,
32 mmol) was treated with I2 (8.2 g, 32 mmol) and
CF3COOAg (7.14 g, 32 mmol) in CHCl3 (100 mL). After
work-up, alcohol 11a was recrystallised from Et2O (8.5 g,
3.1.4. 6-Iodo-2,3-dimethoxybenzyl alcohol (2e) and 5-
iodo-2,3-dimethoxybenzyl alcohol (2e0). According to the
general procedure, alcohol 1d (168 mg, 1 mmol) was
treated with I2 (250 mg, 1 mmol) and CF3COOAg
(220 mg, 1 mmol) in CHCl3 (30 mL). After work-up, flash
column chromatography afforded a mixture of 2e and 2e0 in
a 3:1 ratio, that could not be separated. Data of the mixture
is given (178 mg, 73 and 83% conversion); IR (neat)
1
82%): mp (Et2O) 107–108 8C; IR (neat) 3381 cmK1; H
NMR (CDCl3) 1.52 (s, 1H), 1.79–1.90 (m, 2H), 2.75 (t, JZ
7.8 Hz, 2H), 3.71 (t, JZ6.3 Hz, 2H), 3.84 (s, 3H), 3.85 (s,
3H), 6.75 (s, 1H), 7.20 (s, 1H); 13C NMR (CDCl3) 33.2,
36.5, 55.8, 56.0, 61.8, 87.8, 112.1, 121.5, 136.7, 147.6,
149.2. MS (EI) m/z (rel intensity) 322 (MC, 64), 277(36),
167(16), 152(12), 151(100).
1
3422 cmK1; H NMR (CDCl3) 3.42 (s, 1H, both isomers),
3.71 (s, 3H, minor), 3.73 (s, 3H, both isomers), 3.77 (s, 3H,
major), 4.51 (s, 2H, minor), 4.68 (s, 2H, major), 6.53 (d, JZ
8.7 Hz, 1H, major), 7.03 (d, JZ2.0 Hz, 1H, minor), 7.22 (d,
JZ2.0 Hz, 1H, minor), 7.40 (d, JZ8.7 Hz, 1H, major); 13C
NMR (CDCl3) 55.7 (major), 55.8 (minor), 59.6 (minor),
60.6 (minor), 61.5 (major), 64.2 (major), 86.8, 88.5 (major,
minor), 113.9 (major), 120.7, 129.0 (minor), 134.3 (major),
136.3 (major), 136.5 (minor), 146.2 (minor), 147.9 (major),
152.7 (minor), 152.9 (major). MS (EI) m/z (rel intensity)
295 (MCC1, 10), 294 (MC, 100), 279 (13), 152 (19), 139
(24), 124 (39), 109 (30), 108 (12), 106 (10), 85 (11), 83 (17),
81 (19), 79 (13), 78 (11), 77 (19), 65 (11), 63 (17), 53 (23),
52 (10), 51 (20).
3.2. Synthesis of bromides 3a–g. General procedure
PBr3 (0.19 mL, 2 mmol) was added over a solution of
alcohols 2a–g (1 mmol) in dry CH2Cl2 (10 mL), and the
reaction mixture was stirred at rt for 16 h. Solvent was
evaporated, and the resulting oil was treated with saturated
NaHCO3. The resulting aqueous phase was extracted with
CH2Cl2 (3!15 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo, yielding
bromides 3a–g, which were crystallised from Et2O.
3.2.1. 2-Iodobenzyl bromide (3a).33 According to the
general procedure, alcohol 2a (234 mg, 1 mmol) was treated
with PBr3 (0.19 mL, 2 mmol) in dry CH2Cl2 (10 mL). After
work-up, bromide 3a was recrystallised from Et2O (291 mg,
98%): mp (Et2O) 56–58 8C; 1H NMR (CDCl3) 4.60 (s, 2H),
6.98 (td, JZ7.7, 1.5 Hz, 1H), 7.34 (td, JZ7.5, 0.9 Hz, 1H),
7.47 (dd, JZ7.6, 1.5 Hz, 1H), 7.86 (d, JZ7.8 Hz, 1H); 13C
NMR (CDCl3) 38.8, 100.1, 128.8, 130.1, 130.4, 140.0,
140.1. The rest of the spectroscopic and physical data are
consistent with those described in the literature.33
3.1.5. 2-Iodo-4,5-methylendioxybenzyl alcohol (2f).30
According to the general procedure, alcohol 1f (152 mg,
1 mmol) was treated with I2 (250 mg, 1 mmol) and
CF3COOAg (220 mg, 1 mmol) in CHCl3 (30 mL). After
work-up, alcohol 2f was recrystallised from Et2O (211 mg,
1
76%): mp (Et2O) 107–109 8C; IR (KBr) 3200 cmK1; H
NMR (CDCl3) 2.31 (s, 1H), 4.55 (s, 2H), 5.96 (s, 2H), 6.96
(s, 1H), 7.21 (s, 1H); 13C NMR (CDCl3) 69.1, 85.3, 101.6,
109.0, 118.4, 136.1, 147.8, 148.5. The rest of the spectro-
scopic and physical data are consistent with those described
in the literature.30
3.2.2. 2-Iodo-4,5-dimethylbenzyl bromide (3b). Accord-
ing to the general procedure, alcohol 2b (262 mg, 1 mmol)
was treated with PBr3 (0.19 mL, 2 mmol) in dry CH2Cl2
(10 mL). After work-up, bromide 3b was recrystallised
from Et2O (325 mg, 99%): mp (Et2O) 76–78 8C; IR (KBr)
3.1.6. 2-Iodo-3,4,5-trimethoxybenzyl alcohol (2g).31
According to the general procedure, alcohol 1g (198 mg,
1 mmol) was treated with I2 (250 mg, 1 mmol) and
CF3COOAg (220 mg, 1 mmol) in CHCl3 (30 mL). After
work-up, alcohol 2g was recrystallised from Et2O (305 mg,
94%): mp (Et2O) 52–54 8C; IR (neat) 3420 cmK1; 1H NMR
(CDCl3) 2.75 (s, 1H), 3.83 (s, 6H), 3.84 (s, 3H), 4.59 (s, 2H),
6.89 (s, 1H); 13C NMR (CDCl3) 56.0, 60.7, 60.9, 69.1, 84.2,
107.6, 138.3, 141.0, 152.7, 153.7. The rest of the spectro-
scopic and physical data are consistent with those described
in the literature.31
1
3260 cmK1; H NMR (CDCl3) 2.21 (s, 6H), 4.56 (s, 2H),
7.24 (s, 1H), 7.62 (s, 1H); 13C NMR (CDCl3) 19.0, 19.3,
38.9, 96.3, 131.4, 137.3, 137.5, 139.4, 140.5. MS (EI) m/z
(rel intensity) 326 (MCC2, 10), 324 (MC, 9), 246 (10), 245
(100), 118 (41), 117 (24), 115 (15), 91 (14), 85 (30), 83 (46),
51 (12).
3.2.3. 2-Iodo-5-methoxybenzyl bromide (3c).34 According
to the general procedure, alcohol 2c (264 mg, 1 mmol) was
treated with PBr3 (0.19 mL, 2 mmol) in dry CH2Cl2

3316
J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
(10 mL). After work-up, bromide 3c was recrystallised from
Et2O (280 mg, 86%): mp (Et2O) 111–113 8C; 1H NMR
(CDCl3) 3.80 (s, 3H), 4.54 (s, 2H), 6.59 (dd, JZ8.7, 2.8 Hz,
1H), 7.03 (d, JZ2.8 Hz, 1H), 7.70 (d, JZ8.7 Hz, 1H); 13C
NMR (CDCl3) 38.7, 55.4, 88.3, 116.0, 116.3, 140.4, 140.9,
160.0. The rest of the spectroscopic and physical data are
consistent with those described in the literature.34
chloride (6.3 g, 32.9 mmol) were added over a solution of
alcohol 11a (8.45 g, 27.4 mmol) in dry CH2Cl2 (30 mL) at
0 8C, and the reaction mixture was stirred at rt for 30 min.
The reaction mixture was washed with HCl (5 M, 5 mL).
The resulting aqueous phase was extracted with CH2Cl2
(3!15 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo, yielding 12a, which
was crystallised from Et2O (12.5 g, 98%): mp (Et2O) 109–
1
3.2.4. 2-Iodo-4,5-dimethoxybenzyl bromide (3d).33
According to the general procedure, alcohol 2d (294 mg,
1 mmol) was treated with PBr3 (0.19 mL, 2 mmol) in dry
CH2Cl2 (10 mL). After work-up, bromide 3d was
recrystallised from Et2O (339 mg, 95%): mp (Et2O) 74–
75 8C; 1H NMR (CDCl3) 3.86 (s, 3H), 3.87 (s, 3H), 4.58 (s,
2H), 6.96 (s, 1H), 7.22 (s, 1H); 13C NMR (CDCl3) 39.4,
56.0, 56.2, 88.5, 112.7, 121.8, 132.5, 149.6. The rest of the
spectroscopic and physical data are consistent with those
described in the literature.33
110 8C; H NMR (CDCl3) 2.42 (s, 3H), 3.01 (t, JZ6.9 Hz,
2H), 3.81, 3.83 (s, 3H), 4.20 (t, JZ6.9 Hz, 2H), 6.67 (s, 1H),
7.11 (s, 1H), 7.27 (d, JZ7.9 Hz, 2H), 7.68 (d, JZ7.9 Hz,
2H); 13C NMR (CDCl3) 21.3, 39.2, 55.6, 55.8, 69.0, 87.6,
112.8, 121.2, 127.4, 129.5, 130.9, 132.5, 144.4, 148.2,
148.9. MS (EI) m/z (rel intensity) 462 (MC, 27), 291 (11),
290 (100), 277 (26), 151 (14), 91 (25), 65 (10).
3.2.9. 3-(2-Iodo-4,5-dimethoxyphenyl)propyl methane-
sulfonate (12b). Et3N (1.9 mL, 13.6 mmol) and mesyl
chloride (1.06 mL, 13.6 mmol) were added over a solution
of alcohol 11b (3.66 g, 11.4 mmol) in dry CH2Cl2 (40 mL)
at 0 8C, and the reaction mixture was stirred at rt for 30 min.
The reaction mixture was washed with saturated NaHCO3
(15 mL). The resulting aqueous phase was extracted with
CH2Cl2 (3!15 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo, yielding 12b
(4.1 g, 93%); 1H NMR (CDCl3) 1.79–1.90 (m, 2H), 2.75 (t,
JZ7.8 Hz, 2H), 2.91 (s, 3H), 3.71 (t, JZ6.3 Hz, 2H), 3.84,
3.85 (s, 3H), 6.75 (s, 1H), 7.20 (s, 1H); 13C NMR (CDCl3)
33.2, 36.5, 37.1, 55.8, 56.0, 65.8, 87.8, 112.1, 121.5, 136.7,
147.6, 149.2. MS (EI) m/z (rel intensity) 400 (MC, 100), 304
(22), 289 (10), 277 (92), 177 (39), 151 (31), 146 (22), 91
(18).
3.2.5. 6-Iodo-2,3-dimethoxybenzyl bromide (3e) and 5-
iodo-2,3-dimethoxybenzyl bromide (3e0). According to
the general procedure, a mixture of alcohols 2e/2e0 in a 3:1
ratio (294 mg, 1 mmol) was treated with PBr3 (0.19 mL,
2 mmol) in dry CH2Cl2 (10 mL). After work-up, a mixture
of bromides 3e/3e0 in a 3:1 ratio was obtained, that could not
be separated by chromatographic methods (332 mg, 93%).
Data of the mixture are given: 1H NMR (CDCl3) 3.84 (s, 3H
both isomers), 3.92 (s, 3H minor), 3.95 (s, 3H, major), 4.44
(s, 2H, minor), 4.70 (s, 2H, major), 6.64 (d, JZ8.7 Hz, 1H,
major), 7.13 (d, JZ2.0 Hz, 1H, minor), 7.28 (d, JZ2 Hz,
1H, minor), 7.51 (d, JZ8.7 Hz, 1H, major); 13C NMR
(CDCl3) 26.6 (minor), 33.5 (major), 55.8, 61.0 (major),
56.0, 60.8 (minor), 86.4 (minor), 89.1 (major), 114.5
(major), 121.9, 131.1 (minor), 133.6, 134.2 (major,
minor), 134.5 (major), 147.3 (minor), 148.1, 153.1
(major), 153.3 (minor). MS (EI) m/z (rel intensity) 358
(MCC2, 16), 356 (MC, 15), 277 (80), 262 (58), 232 (10),
92 (17), 90 (24), 87 (12), 85 (68), 83 (100), 77 (15), 64 (22),
63 (20).
3.3. Alkylation reactions. General procedure for the
synthesis of N-benzyl-, N-phenethyl-, and N-phenyl-
propylpyrroles 5–7, 13, and 14
Pyrrole-2-carboxamide 4a, 4b or 4c (1 mmol) was added
over a suspension of powdered KOH (224 mg, 4 mmol) in
DMSO (5 mL). The mixture was stirred at rt for 2 h,
bromide 3a–g, tosylate 12a, or mesylate 12b (2 mmol) was
added, and the reaction mixture was stirred for 3 h. H2O
(10 mL) was added and the resulting aqueous phase was
extracted with CH2Cl2 (3!10 mL). The combined organic
extracts were washed with brine (3!10 mL), dried
(Na2SO4), and concentrated in vacuo. Flash column
chromatography (silicagel) afforded N-benzylpyrroles 5, 6,
and 7, N-phenethylpyrroles or N-phenylpropylpyrroles 13 or
14.
3.2.6. 2-Iodo-4,5-methylendioxybenzyl bromide (3f).30
According to the general procedure, alcohol 2f (278 mg,
1 mmol) was treated with PBr3 (0.19 mL, 2 mmol) in dry
CH2Cl2 (10 mL). After work-up, bromide 3f was
recrystallised from Et2O (310 mg, 91%): mp (Et2O) dec.;
1H NMR (CDCl3) 4.55 (s, 2H), 5.99 (s, 2H), 6.96 (s, 1H),
7.24 (s, 1H); 13C NMR (CDCl3) 39.5, 88.8, 102.0, 110.0,
119.0, 133.3, 148.6. The rest of the spectroscopic and physical
data are consistent with those described in the literature.30
3.2.7. 2-Iodo-3,4,5-trimethoxybenzyl bromide (3g). Alco-
hol 2g (324 mg, 1 mmol) was treated with HBr (45%)
(10 mL) at K10 8C under argon for 48 h. The precipitate
obtained was filtered and washed with H2O. The resulting
bromide 3g was recrystallised from Et2O (298 mg, 77%):
mp (Et2O) 78–80 8C; 1H NMR (CDCl3) 3.86 (s, 9H), 4.62 (s,
2H), 6.88 (s, 1H); 13C NMR (CDCl3) 39.5, 56.1, 60.7, 60.9,
88.3, 109.5, 135.3, 142.0, 153.4, 153.6. MS (EI) m/z (rel
intensity) 388 (MCC2, 4), 386 (MC, 4), 165 (21), 135 (11),
90 (13), 79 (16), 77 (11), 66 (10), 63 (12), 53 (10), 51 (25).
3.3.1. 1-(2-Iodobenzyl)pyrrole-2-carboxylic acid diethyl
amide (5a). According to the general procedure, N,N-
diethyl-pyrrole-2-carboxamide 4a (165 mg, 1 mmol) was
treated with KOH (224 mg, 4 mmol) in DMSO (5 mL), and
bromide 3a (595 mg, 2 mmol). After work-up, flash column
chromatography (silicagel, 30% hexane/AcOEt) afforded 5a
as a colourless oil (227 mg, 60%); IR (CHCl3) 1616 cmK1
;
1H NMR (CDCl3) 1.10 (t, JZ7.1 Hz, 6H), 3.43 (q, JZ
7.1 Hz, 4H), 5.32 (s, 2H), 6.13 (dd, JZ3.7, 2.6 Hz, 1H),
6.38 (dd, JZ3.7, 1.7 Hz, 1H), 6.69 (dd, JZ7.7, 1.3 Hz, 1H),
6.74 (dd, JZ2.6, 1.7 Hz, 1H), 6.91 (td, JZ7.7, 1.4 Hz, 1H),
7.21 (td, JZ7.7, 1.3 Hz, 1H), 7.79 (dd, JZ7.7, 1.4 Hz, 1H);
13C NMR (CDCl3) 13.4, 41.4, 56.2, 97.5, 107.2, 111.0,
3.2.8. 2-(2-Iodo-4,5-dimethoxyphenyl)ethyl p-toluen-
sulfonate (12a). Et3N (4.6 mL, 32.9 mmol) and tosyl

J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
3317
125.1, 126.2, 128.2, 128.3, 128.9, 139.1, 140.8, 163.4. MS
(EI) m/z (rel intensity) 383 (MCC1, 8), 382 (MC, 39), 282
(15), 256 (13), 255 (70), 217 (28), 184 (25), 183 (100), 182
(42), 156 (29), 155 (19), 154 (22), 127 (13), 100 (16), 91
(12), 90 (37), 89 (17), 72 (34). Anal. Calcd for C16H19IN2O:
C, 50.28; H, 5.01; N, 7.33. Found: C, 49.99; H, 5.10; N,
7.29.
(29), 200 (12), 150 (18), 107 (15), 100 (36), 94 (11), 92 (15),
85 (10), 83 (13), 79 (10), 77 (20), 72 (56), 64 (14), 63 (13),
56 (14), 51 (12). Anal. Calcd for C18H23IN2O3: C, 48.88; H,
5.24; N, 6.33. Found: C, 48.60; H, 5.36; N, 6.24.
3.3.5. 1-(6-Iodo-2,3-dimethoxybenzyl)pyrrole-2-car-
boxylic acid diethyl amide (5e). According to the general
procedure, N,N-diethyl-pyrrole-2-carboxamide 4a (600 mg,
3.6 mmol) was treated with KOH (780 mg, 13.9 mmol) in
DMSO (15 mL), and a mixture of bromides 3e/3e0 in a 2:1
ratio (2.5 g, 7 mmol). After work-up, flash column chroma-
tography (silicagel, 30% hexane/AcOEt) afforded 5e as a
3.3.2. 1-(2-Iodo-4,5-dimethylbenzyl)pyrrole-2-car-
boxylic acid diethyl amide (5b). According to the general
procedure, N,N-diethyl-pyrrole-2-carboxamide 4a (260 mg,
1.6 mmol) was treated with KOH (340 mg, 6.1 mmol) in
DMSO (6 mL), and bromide 3b (1.03 g, 3.2 mmol). After
work-up, flash column chromatography (silicagel, 20%
hexane/AcOEt) afforded 5b as a colourless oil (530 mg,
1
colourless oil (400 mg, 25%); IR (CHCl3) 1613 cmK1; H
NMR (CDCl3) 1.23 (t, JZ7.1 Hz, 6H), 3.57 (q, JZ7.1 Hz,
4H), 3.68 (s, 3H), 3.81 (s, 3H), 5.39 (s, 2H), 5.97 (dd, JZ
4.0, 2.8 Hz, 1H), 6.29 (dd, JZ4.0, 1.6 Hz, 1H), 6.49 (dd,
JZ2.8, 1.6 Hz, 1H), 6.64 (d, JZ8.7 Hz, 1H), 7.51 (d, JZ
8.7 Hz, 1H); 13C NMR (CDCl3) 13.5, 41.9, 50.5, 55.7, 60.8,
89.6, 106.6, 110.0, 114.1, 123.1, 126.7, 133.5, 134.5, 148.6,
153.1, 164.0. MS (EI) m/z (rel intensity) 442 (MC, 16), 262
(15), 87 (11), 85 (64), 83 (100), 72 (13). Anal. Calcd for
C18H23IN2O3: C, 48.88; H, 5.24; N, 6.33. Found: C, 49.03;
H, 4.89; N, 5.90.
1
83%); IR (CHCl3) 1618 cmK1; H NMR (CDCl3) 1.11 (t,
JZ7.1 Hz, 6H), 2.09 (s, 3H), 2.13 (s, 3H), 3.45 (q, JZ
7.1 Hz, 4H), 5.25 (s, 2H), 6.09 (dd, JZ4.0, 2.8 Hz, 1H),
6.35 (dd, JZ4.0, 2.0 Hz, 1H), 6.59 (s, 1H), 6.72 (dd, JZ2.8,
2.0 Hz, 1H), 7.55 (s, 1H); 13C NMR (CDCl3) 13.5, 18.8,
19.4, 41.3, 55.6, 94.4, 107.0, 110.9, 124.9, 126.1, 129.9,
139.8, 136.9, 137.9, 163.6. MS (EI) m/z (rel intensity) 410
(MC, 17), 284 (23), 283 (100), 245 (31), 212 (17), 211 (57),
210 (44), 196 (17), 190 (17), 184 (19), 183 (13), 168 (12),
119 (10), 118 (23), 117 (17), 115 (13), 100 (17), 91 (12), 85
(10), 83 (16), 72 (29). Anal. Calcd for C18H23IN2O: C,
52.69; H, 5.65; N, 6.83. Found: C, 52.44; H, 5.21; N, 7.02.
3.3.6. 1-(2-Iodo-4,5-methylendioxybenzyl)pyrrole-2-car-
boxylic acid diethyl amide (5f). According to the general
procedure, N,N-diethyl-pyrrole-2-carboxamide 4a (710 mg,
4.3 mmol) was treated with KOH (1.05 g, 18.7 mmol) in
DMSO (6 mL), and bromide 3f (2.9 g, 8.6 mmol). After
work-up, flash column chromatography (silicagel, 30%
hexane/AcOEt) afforded 5f as a colourless oil (1.53 mg,
3.3.3. 1-(2-Iodo-5-methoxybenzyl)pyrrole-2-carboxylic
acid diethyl amide (5c). According to the general
procedure,
N,N-diethyl-pyrrole-2-carboxamide
4a
1
84%); IR (CHCl3) 1615 cmK1; H NMR (CDCl3) 1.14 (t,
(150 mg, 0.9 mmol) was treated with KOH (250 mg,
4.4 mmol) in DMSO (5 mL), and bromide 3c (610 mg,
1.9 mmol). After work-up, flash column chromatography
(silicagel, 30% hexane/AcOEt) afforded 5c as a colourless
JZ7.1 Hz, 6H), 3.46 (q, JZ7.1 Hz, 4H), 5.22 (s, 2H), 5.89
(s, 2H), 6.10 (dd, JZ4.0, 2.8 Hz, 1H), 6.34 (s, 1H), 6.36 (dd,
JZ4.0, 1.6 Hz, 1H), 6.73 (dd, JZ2.8, 1.6 Hz, 1H), 7.19 (s,
1H); 13C NMR (CDCl3) 13.2, 41.0, 55.7, 85.4, 101.3, 107.0,
108.5, 110.8, 118.0, 124.6, 125.7, 134.0, 147.3, 148.3,
163.1. MS (EI) m/z (rel intensity) 426 (MC, 2), 299 (45),
261 (23), 227 (15), 226 (16), 206 (9), 100 (9), 87 (13), 85
(69), 83 (100), 76 (11), 72 (13). Anal. Calcd for
C17H19IN2O3: C, 47.90; H, 4.49; N, 6.57. Found: C,
48.01; H, 4.65; N, 6.12.
oil (350 mg, 94%); IR (CHCl3) 1617 cmK1 1H NMR
;
(CDCl3) 1.10 (t, JZ7.1 Hz, 6H), 3.45 (q, JZ7.1 Hz, 4H),
3.64 (s, 3H), 5.27 (s, 2H), 6.12 (dd, JZ3.6, 2.8 Hz, 1H),
6.26 (d, JZ2.8 Hz, 1H), 6.38 (dd, JZ3.6, 1.6 Hz, 1H),
6.50–6.52 (m, 1H), 6.73 (dd, JZ2.8, 1.6 Hz, 1H), 7.63 (d,
JZ8.7 Hz, 1H); 13C NMR (CDCl3) 13.4, 41.3, 55.1, 56.1,
85.8, 107.2, 111.1, 114.5, 125.1, 126.1, 139.5, 141.9, 160.0,
163.3. MS (EI) m/z (rel intensity) 412 (MC, 3), 286 (24),
285 (100), 214 (14), 213 (41), 212 (23), 192 (23), 186 (13),
170 (17), 120 (15), 100 (14), 85 (23), 83 (39), 72 (20). Anal.
Calcd for C17H21IN2O2: C, 49.52; H, 5.13; N, 6.79. Found:
C, 49.23; H, 5.41; N, 6.59.
3.3.7. 1-(2-Iodo-3,4,5-trimethoxybenzyl)pyrrole-2-car-
boxylic acid diethyl amide (5g). According to the general
procedure, N,N-diethyl-pyrrole-2-carboxamide 4a (150 mg,
0.9 mmol) was treated with KOH (240 mg, 4.3 mmol) in
DMSO (6 mL), and bromide 3g (700 mg, 1.8 mmol). After
work-up, flash column chromatography (silicagel, 30%
hexane/AcOEt) afforded 5g as a colourless oil (240 mg,
3.3.4. 1-(2-Iodo-4,5-dimethoxybenzyl)pyrrole-2-car-
boxylic acid diethyl amide (5d). According to the general
procedure, N,N-diethyl-pyrrole-2-carboxamide 4a (884 mg,
2.0 mmol) was treated with KOH (448 mg, 8.0 mmol) in
DMSO (20 mL), and bromide 3d (1.5 g, 4.2 mmol). After
work-up, flash column chromatography (silicagel, 40%
hexane/AcOEt) afforded 5d as a colourless oil (1.72 mg,
1
56%); IR (CHCl3) 1618 cmK1; H NMR (CDCl3) 1.09 (t,
JZ7.1 Hz, 6H), 3.43 (q, JZ7.1 Hz, 4H), 3.63 (s, 3H), 3.78
(s, 3H), 3.81 (s, 3H), 5.27 (s, 2H), 6.08–6.10 (m, 1H), 6.15
(s, 1H), 6.34–6.36 (m, 1H), 6.73 (broad s, 1H); 13C NMR
(CDCl3) 13.4, 41.4, 55.7, 56.2, 60.6, 60.7, 85.4, 107.1,
107.8, 111.0, 125.0, 126.1, 136.4, 141.0, 152.6, 153.6,
163.2. MS (EI) m/z (rel intensity) 346 (12), 345 (38), 307
(16), 252 (48), 181 (24), 100 (18), 87 (12), 85 (72), 83 (100),
72 (25). Anal. Calcd for C19H25IN2O4: C, 48.32; H, 5.33; N,
5.93. Found: C, 48.17; H, 5.01; N, 5.12.
1
73%); IR (CHCl3) 1616 cmK1; H NMR (CDCl3) 1.11 (t,
JZ7.1 Hz, 6H), 3.44 (q, JZ7.1 Hz, 4H), 3.68 (s, 3H), 3.80
(s, 3H), 5.24 (s, 2H), 6.08–6.09 (m, 1H), 6.34 (dd, JZ3.6,
1.5 Hz, 1H), 6.44 (s, 1H), 6.72 (dd, JZ2.5, 1.5 Hz, 1H),
7.17 (s, 1H); 13C NMR (CDCl3) 13.5, 41.2, 55.6, 55.6, 56.0,
86.1, 107.1, 111.0, 111.9, 121.3, 124.8, 126.2, 133.2, 148.7,
149.4, 163.5. MS (EI) m/z (rel intensity) 442 (MC, 2), 316
(21), 315 (100), 277 (62), 244 (22), 243 (22), 242 (33), 222
3.3.8. 1-(2-Iodobenzyl)pyrrole-2-carboxylic acid meth-
oxy methyl amide (6a). According to the general

3318
J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
procedure, N-methoxy-N-methylpyrrole-2-carboxamide 4b
(154 mg, 1 mmol) was treated with KOH (224 mg, 4 mmol)
in DMSO (5 mL), and bromide 3a (594 mg, 2 mmol). After
work-up, flash column chromatography (silicagel, 20%
hexane/AcOEt) afforded 6a as a colourless oil, that was
crystallised from Et2O (333 mg, 90%): mp (Et2O) 100–
102 8C; IR (CHCl3) 1623 cmK1; 1H NMR (CDCl3) 3.27 (s,
3H), 3.66 (s, 3H), 5.52 (s, 2H), 6.23(dd, JZ4.0, 2.8 Hz, 1H),
6.48 (dd, JZ7.9, 1.2 Hz, 1H,), 6.79 (dd, JZ2.8, 1.8 Hz),
6.90–6.93 (m, 1H), 7.02 (dd, JZ4.0, 1.8 Hz, 1H), 7.18–7.24
(m, 1H), 7.82 (dd, JZ7.9, 1.2 Hz, 1H); 13C NMR (CDCl3)
33.5, 57.3, 60.8, 96.9, 108.2, 116.6, 123.1, 127.1, 127.5,
128.3, 128.6, 138.9, 161.8. MS (EI) m/z (rel intensity) 370
(MC, 5), 311 (7), 310 (51), 217 (15), 184 (12), 183 (10), 182
(10), 154 (10), 127 (5), 90 (14), 89 (7). Anal. Calcd for
C14H15IN2O2: C, 45.42; H, 4.08; N, 7.57. Found: C, 45.42;
H, 4.27; N, 7.25.
colourless oil, that was crystallised from pentane (409 g,
1
95%); IR (CHCl3) 1623 cmK1; H NMR (CDCl3) 3.30 (s,
3H), 3.65 (s, 3H), 3.67 (s, 3H), 3.84 (s, 3H), 5.46 (s, 2H),
6.19 (dd, JZ4.0, 2.8 Hz, 1H), 6.28 (s, 1H), 6.82 (dd, JZ2.8,
1.8 Hz, 1H), 6.97 (dd, JZ4.0, 1.8 Hz, 1H), 7.22 (s, 1H); 13C
NMR (CDCl3) 33.7, 55.6, 56.1, 56.6, 60.9, 85.6, 108.1,
111.1, 116.6, 121.3, 123.2, 127.4, 133.6, 148.6, 149.5,
162.2. MS (EI) m/z (rel intensity) 430 (MC, 6), 370 (22),
243 (100), 83 (29). Anal. Calcd for C16H19IN2O4: C, 44.67;
H, 4.45; N, 6.51. Found: C, 45.12; H, 4.44; N, 5.96.
3.3.12. 1-(6-Iodo-2,3-dimethoxybenzyl)pyrrole-2-car-
boxylic acid methoxy methyl amide (6e). According to
the general procedure, N-methoxy-N-methylpyrrole-2-car-
boxamide 4b (154 mg, 1 mmol) was treated with KOH
(224 mg, 4 mmol) in DMSO (5 mL), and a mixture of
bromides 3e/3e0 in a 3:1 ratio (714 mg, 2 mmol). After
work-up, flash column chromatography (silicagel, 20%
hexane/AcOEt) afforded 6e as a colourless oil, that was
crystallised from pentane (262 mg, 61%): mp (pentane) 94–
96 8C; IR (KBr) 1622 cmK1; 1H NMR (CDCl3) 3.39 (s, 3H),
3.70 (s, 3H), 3.72 (s, 3H), 3.84 (s, 3H), 5.62 (s, 2H), 6.03
(dd, JZ4.0, 2.6 Hz, 1H), 6.52 (dd, JZ2.6, 1.8 Hz, 1H), 6.68
(d, JZ8.7 Hz, 1H), 6.86 (dd, JZ4.0, 1.8 Hz, 1H), 7.56 (d,
JZ8.7 Hz, 1H); 13C NMR (CDCl3) 34.1, 51.2, 56.7, 60.8,
60.9, 89.9, 107.3, 114.2, 115.5, 123.9, 125.0, 133.5, 134.5,
148.7, 153.1, 162.7. MS (EI) m/z (rel intensity) 430 (MC,1),
370 (25), 262 (14), 244 (16), 243 (100), 228 (17), 212 (25),
200 (7), 108 (8), 92 (7), 90 (8). Anal. Calcd for
C16H19IN2O4: C, 44.67; H, 4.45; N, 6.51. Found: C,
44.55; H, 4.46; N, 6.34.
3.3.9. 1-(2-Iodo-4,5-dimethylbenzyl)pyrrole-2-car-
boxylic acid methoxy methyl amide (6b). According to
the general procedure, N-methoxy-N-methylpyrrole-2-car-
boxamide 4b (154 mg, 1 mmol) was treated with KOH
(224 mg, 4 mmol) in DMSO (5 mL), and bromide 3b
(645 mg, 2 mmol). After work-up, flash column chroma-
tography (silicagel, 10% hexane/AcOEt) afforded 6b as a
colourless oil, that was crystallised from Et2O (310 mg,
1
78%): mp (Et2O) 76–79 8C; IR (CHCl3) 1625 cmK1; H
NMR (CDCl3) 2.08 (s, 3H), 2.16 (s, 3H), 3.30 (s, 3H), 3.66
(s, 3H,), 5.46 (s, 2H), 6.19 (dd, JZ4.0, 2.4 Hz, 1H), 6.38 (s,
1H), 6.76 (dd, JZ2.4, 1.8 Hz, 1H), 6.99 (dd, JZ4.0, 1.8 Hz,
1H), 7.59(s, 1H); 13C NMR (CDCl3) 18.8, 19.5, 33.7, 56.8,
60.9, 93.7, 108.8, 116.5; 123.3, 127.3, 128.9; 137.1, 137.8,
138.3, 139.8, 162.1. MS (EI) m/z (rel intensity) 398 (MC, 1),
338 (25), 245 (19), 241 (8), 221 (18), 211 (100), 210 (7), 196
(24), 168 (6), 118 (15), 117 (11), 115 (8), 91 (7), 83 (6).
3.3.13. 1-(2-Iodo-4,5-methylendioxybenzyl)pyrrole-2-
carboxylic acid methoxy methyl amide (6f). According
to the general procedure, N-methoxy-N-methylpyrrole-2-
carboxamide 4b (154 mg, 1 mmol) was treated with KOH
(224 mg, 4 mmol) in DMSO (5 mL), and bromide 3f
(682 mg, 2 mmol). After work-up, flash column chroma-
tography (silicagel, 30% hexane/AcOEt) afforded 6f as a
3.3.10. 1-(2-Iodo-5-methoxybenzyl)pyrrole-2-carboxylic
acid methoxy methyl amide (6c). According to the general
procedure, N-methoxy-N-methylpyrrole-2-carboxamide 4b
(154 mg, 1 mmol) was treated with KOH (224 mg, 4 mmol)
in DMSO (5 mL), and bromide 3c (654 mg, 2 mmol). After
work-up, flash column chromatography (silicagel, 20%
hexane/AcOEt) afforded 6b as a colourless oil, that was
crystallised from Et2O (332 mg, 83%): mp (Et2O) 84–85 8C;
1
colourless oil (319 mg, 77%); IR (KBr) 1624 cmK1; H
NMR (CDCl3) 3.30 (s, 3H), 3.67 (s, 3H), 5.43 (s, 2H), 5.90
(s, 2H), 6.10 (s, 1H), 6.21 (dd, JZ4.0, 2.8 Hz, 1H), 6.78 (dd,
JZ2.8, 1.6 Hz, 1H), 7.01 (dd, JZ4.0, 1.6 Hz, 1H), 7.23 (s,
1H); 13C NMR (CDCl3) 33.6, 57.2, 61.0, 84.8, 101.5, 107.9,
108.4, 116.8, 118.3, 123.1, 127.4, 134.8, 147.5, 148.7,
161.3. MS (EI) m/z (rel intensity) 414 (MC, 2), 354 (21),
287 (11), 261 (15), 227 (100), 134 (6), 76 (8). Anal. Calcd
for C15H15IN2O4: C, 43.50; H, 3.65; N, 6.76. Found: C,
43.53; H, 3.69; N, 6.54.
1
IR (CHCl3) 1663 cmK1; H NMR (CDCl3) 3.28 (s, 3H),
3.64 (s, 3H), 3.66 (s, 3H,), 5.48 (s, 2H), 6.07 (d, JZ3.0 Hz,
1H), 6.22 (dd, JZ4.0, 2.6 Hz, 1H), 6.53 (dd, JZ8.7, 3.0 Hz,
1H), 6.80 (dd, JZ2.6, 1.8 Hz, 1H), 7.02 (dd, JZ4.0, 1.8 Hz,
1H), 7.67 (d, JZ8.7 Hz, 1H); 13C NMR (CDCl3) 33.7, 55.1,
57.3, 61.0, 85.3, 108.3, 113.8, 114.3, 116.8, 123.3, 127.7,
139.5, 142.5, 160.2, 162.0. MS (EI) m/z (rel intensity) 400
(MC, 2), 340 (21), 273 (6), 247 (6), 214 (15), 213 (100), 212
(9), 182 (5), 170 (11), 120 (6), 93 (5), 77 (5). Anal. Calcd for
C15H17IN2O3: C, 45.02; H, 4.28; N, 7.00. Found: C, 44.73;
H, 4.20; N, 6.94.
3.3.14. 1-(2-Iodo-3,4,5-trimethoxybenzyl)pyrrole-2-car-
boxylic acid methoxy methyl amide (6g). According to
the general procedure, N-methoxy-N-methylpyrrole-2-car-
boxamide 4b (154 mg, 1 mmol) was treated with KOH
(224 mg, 4 mmol) in DMSO (5 mL), and bromide 3g
(756 mg, 2 mmol). After work-up, flash column chroma-
tography (silicagel, 20% hexane/AcOEt) afforded 6g as a
colourless oil, that was crystallised from pentane (336 mg,
3.3.11. 1-(2-Iodo-4,5-dimethoxybenzyl)pyrrole-2-car-
boxylic acid methoxy methyl amide (6d). According to
the general procedure, N-methoxy-N-methylpyrrole-2-car-
boxamide 4b (154 mg, 1 mmol) was treated with KOH
(224 mg, 4 mmol) in DMSO (5 mL), and bromide 3d
(714 mg, 2 mmol) after work-up, flash column chromato-
graphy (silicagel, 20% hexane/AcOEt) afforded 6d as a
1
73%): mp (pentane) 80–82 8C; IR (KBr) 1624 cmK1; H
NMR (CDCl3) 3.30 (s, 3H), 3.63 (s, 3H), 3.67 (s, 3H), 3.83
(s, 3H), 3.88 (s, 3H), 5.50 (s, 2H), 5.98 (s, 2H), 6.22 (dd, JZ
4.0, 2.6 Hz, 1H), 6.82 (dd, JZ2.6, 1.8 Hz, 1H), 7.00 (dd,
JZ4.0, 1.8 Hz, 1H); 13C NMR (CDCl3) 33.4, 55.5, 57.1,

J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
3319
60.4, 60.6, 60.7, 84.5, 106.8, 108.0, 116.4, 123.0, 127.5,
140.7, 156.8, 152.5, 153.7, 161.8. MS (EI) m/z (rel intensity)
460 (MC,1), 400 (12), 334 (8), 333 (39), 307 (21), 274 (17),
273 (100), 272 (6), 259 (13), 258 (83), 240 (22), 230 (7), 227
(12), 210 (8), 165 (6). Anal. Calcd for C17H21IN2O5: C,
44.36; H, 4.60; N, 6.09. Found: C, 45.13; H, 4.64; N, 5.71.
(16), 206 (25), 170 (11), 120 (10), 114 (10), 70 (13). Anal.
Calcd for C17H19IN2O3: C, 47.90; H, 4.49; N, 6.57. Found:
C, 47.81; H, 4.42; N, 6.45.
3.3.18. 1-(2-Iodo-4,5-dimethoxybenzyl)pyrrole-2-car-
boxylic acid morpholine amide (7d). According to the
general procedure, pyrrole-2-carboxamide 4c (446 mg,
2.5 mmol) was treated with KOH (560 mg, 9.9 mmol) in
DMSO (5 mL), and bromide 3d (1.77 g, 4.9 mmol) after
work-up, flash column chromatography (silicagel, 70%
hexane/AcOEt) afforded 7d as a colourless oil (1.05 g,
93%); IR (CHCl3) 1619 cmK1; 1H NMR (CDCl3) 3.42–3.43
(m, 4H), 3.52–3.54 (m, 4H), 3.55 (s, 3H), 3.67 (s, 3H), 5.13
(s, 2H), 5.97 (dd, JZ3.6, 2.8 Hz, 1H), 6.19 (dd, JZ3.6,
1.6 Hz, 1H), 6.34 (s, 1H), 6.66 (dd, JZ2.8, 1.6 Hz, 1H),
7.08 (s, 1H); 13C NMR (CDCl3) 45.0, 55.1, 55.2, 55.6, 66.3,
85.8, 106.9, 111.6, 112.3, 120.9, 124.3, 125.3, 132.5, 148.4,
148.9, 162.3. MS (EI) m/z (rel intensity) 456 (MC, 3), 330
(19), 329 (100), 277 (52), 243 (17), 242 (16), 236 (26), 150
(10), 114 (11), 70 (14).
3.3.15. 1-(2-Iodobenzyl)pyrrole-2-carboxylic acid mor-
pholine amide (7a). According to the general procedure,
pyrrole-2-carboxamide 4c (1.34 g, 7.4 mmol) was treated
with KOH (1.66 g, 29.7 mmol) in DMSO (35 mL), and
bromide 3a (4.41 g, 14.8 mmol) after work-up, flash column
chromatography (silicagel, 50% hexane/AcOEt) afforded
7a as a colourless oil, that was crystallised from ethyl
ether (2.00 g, 63%): mp (Et2O) 96–98 8C; IR (CHCl3)
1
1619 cmK1; H NMR (CDCl3) 3.54–3.58 (m, 4H), 3.67–
3.71 (m, 4H), 5.35 (s, 2H), 6.16 (dd, JZ3.8, 2.8 Hz, 1H),
6.37 (dd, JZ3.8, 1.6 Hz, 1H), 6.68 (dd, JZ7.9, 1.2 Hz, 1H),
6.97 (dd, JZ2.8, 1.6 Hz, 1H), 6.95 (td, JZ7.9, 1.2 Hz, 1H),
7.22 (td, JZ7.5, 1.2 Hz, 1H), 7.82 (dd, JZ7.5, 1.2 Hz, 1H);
13C NMR (CDCl3) 45.5, 56.3, 66.8, 97.6, 107.5, 112.0,
124.8, 125.9, 128.2, 128.4, 129.1, 139.3, 140.7, 162.7. MS
(EI) m/z (rel intensity) 397 (MCC1, 10), 396 (MC, 55), 282
(15), 269 (70), 217 (23), 184 (24), 183 (100), 182 (42), 155
(15), 154 (17), 90 (31), 70 (17). Anal. Calcd for
C16H17IN2O2: C, 48.50; H, 4.32; N, 7.07. Found: C,
48.21; H, 4.43; N, 6.72.
3.3.19. 1-(6-Iodo-2,3-dimethoxybenzyl)pyrrole-2-car-
boxylic acid morpholine amide (7e). According to the
general procedure, pyrrole-2-carboxamide 4c (321 mg,
1.8 mmol) was treated with KOH (400 mg, 7.10mmol) in
DMSO (10 mL), and a mixture of bromides 3e/3e in a 2.2/1
ratio (1.27 g, 3.5 mmol). After work-up, flash column
chromatography (silicagel, 50% hexane/AcOEt) afforded
7e as a white solid that was crystallised from pentane.
(413 mg, 50%): mp (pentane) 148–150 8C; IR (KBr)
3.3.16. 1-(2-Iodo-4,5-dimethylbenzyl)pyrrole-2-car-
boxylic acid morpholine amide (7b). According to the
general procedure, pyrrole-2-carboxamide 4c (118 mg,
0.65 mmol) was treated with KOH (147 mg, 2.6 mmol) in
DMSO (10 mL), and bromide 3b (425 mg, 1.31 mmol).
After work-up, flash column chromatography (silicagel,
40% hexane/AcOEt) afforded 7b as a colourless oil
1
1618 cmK1; H NMR (CDCl3) 3.68 (s, 3H), 3.68–3.70 (m,
4H), 3.75–3.77 (m, 4H), 3.79 (s, 3H), 5.42 (s, 2H), 5.97 (dd,
JZ3.6, 2.4 Hz, 1H), 6.23 (dd, JZ3.6, 1.6 Hz, 1H), 6.59 (dd,
JZ2.4, 1.6 Hz, 1H), 6.63 (d, JZ8.7 Hz, 1H), 7.50 (d, JZ
8.7 Hz, 1H); 13C NMR (CDCl3) 45.8, 50.4, 55.8, 60.9, 66.9,
89.5, 107.1, 112.1, 114.3, 124.1, 125.4, 133.6, 134.7, 148.8,
153.2, 163.5. MS (EI) m/z (rel intensity) 456 (MC, 6), 330
(22), 391 (100), 262 (10), 243 (13), 236 (24), 114 (11), 70
(15).
(271 mg, 95%); IR (CHCl3) 1621 cmK1
;
1H NMR
(CDCl3) 2.09 (s, 3H), 2.14 (s, 3H), 3.52–3.56 (m, 4H),
3.66–3.69 (m, 4H), 5.26 (s, 2H), 6.10 (dd, JZ3.6, 2.7 Hz,
1H), 6.32 (dd, JZ3.6, 1.6 Hz, 1H), 6.54 (s, 1H), 6.75 (dd,
JZ2.7, 1.6 Hz, 1H), 7.56 (s, 1H); 13C NMR (CDCl3) 18.6,
19.3, 45.4, 55.4, 66.6, 94.2, 107.1, 112.5, 124.6, 125.6,
129.6, 136.8, 137.6, 137.9, 139.7, 162.7. MS (EI) m/z (rel
intensity) 424 (MC, 9), 298 (21), 297 (100), 245 (21), 212
(11), 211 (46), 210 (29), 204 (21), 196 (11), 118 (11), 70 (9).
Anal. Calcd for C18H21IN2O2: C, 50.96; H, 4.99; N, 6.60.
Found: C, 50.87; H, 4.63; N, 6.72.
3.3.20. 1-(2-Iodo-4,5-methylendioxybenzyl)pyrrole-2-
carboxylic acid morpholine amide (7f). According to the
general procedure, pyrrole-2-carboxamide 4c (53 mg,
0.3 mmol) was treated with KOH (66 mg, 1.2 mmol) in
DMSO (5 mL), and bromide 3f (200 mg, 0.6 mmol). After
work-up, flash column chromatography (silicagel, 50%
hexane/AcOEt) afforded 7f as a colourless oil that was
crystallised from diethyl ether (90 mg, 68%): mp (Et2O)
3.3.17. 1-(2-Iodo-5-methoxybenzyl)pyrrole-2-carboxylic
acid morpholine amide (7c). According to the general
procedure, pyrrole-2-carboxamide 4c (597 mg, 3.3 mmol)
was treated with KOH (744 mg, 13.2 mmol) in DMSO
(15 mL), and bromide 3c (2.17 g, 6.6 mmol). After work-
up, flash column chromatography (silicagel, 40% hexane/
AcOEt) afforded 7c as a white solid, that was crystallised
from ethyl ether (1.22 g, 86%): mp (Et2O) 96–98 8C; IR
1
134–138 8C; IR (CHCl3) 1618 cmK1; H NMR (CDCl3)
3.58–3.62 (m, 4H), 3.70–3.73 (m, 4H), 5.25 (s, 2H), 5.91 (s,
2H), 6.13 (dd, JZ3.8, 2.8 Hz, 1Hl), 6.31 (s, 1H), 6.33 (dd,
JZ3.8, 1.6 Hz, 1H), 6.77 (dd, JZ2.8, 1.6 Hz, 1H), 7.22 (s,
1H); 13C NMR (CDCl3) 45.5, 55.9, 66.8, 85.6, 101.6, 107.5,
108.6, 112.9, 118.4, 124.6, 125.7, 134.1, 147.7, 148.6,
162.7. MS (EI) m/z (rel intensity) 440 (MC, 2), 314 (21),
313 (100), 261 (44), 227 (31), 226 (22), 220 (23), 134 (12),
114 (12), 76 (15), 70 (15). Anal. Calcd for C17H17IN2O4: C,
46.38; H, 3.89; N, 6.36. Found: C, 46.02; H, 3.74; N, 5.96.
1
(KBr) 1619 cmK1; H NMR (CDCl3) 3.49–3.53 (m, 4H),
3.62 (s, 3H), 3.64–3.67 (m, 4H), 5.27 (s, 2H), 6.11 (dd, JZ
3.7, 2.8 Hz, 1H), 6.22 (d, JZ2.8 Hz, 1H), 6.32 (dd, JZ3.7,
1.6 Hz, 1H), 6.51 (dd, JZ8.7, 2.8 Hz, 1H), 6.76 (dd, JZ2.8,
1.6 Hz, 1H), 7.63 (d, JZ8.7 Hz, 1H); 13C NMR (CDCl3)
45.7, 55.3, 56.3, 67.0, 85.8, 107.4, 112.9, 114.3, 114.9,
124.7, 125.9, 139.7, 141.8, 160.1, 162.7. MS (EI) m/z (rel
intensity) 426 (MC, 11), 299 (100), 214 (11), 213 (37), 212
3.3.21. 1-(2-Iodo-3,4,5-trimethoxybenzyl)pyrrole-2-car-
boxylic acid morpholine amide (7g). According to the
general procedure, pyrrole-2-carboxamide 4c (354 mg,
1.9 mmol) was treated with KOH (441 mg, 7.8 mmol) in

3320
J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
DMSO (10 mL), and bromide 3g (1.52 mg, 3.9 mmol).
After work-up, flash column chromatography (silicagel,
60% hexane/AcOEt) afforded 7g as a colourless oil
162.9. MS (EI) m/z (rel intensity) 470 (MC, 1), 344 (18),
343 (75), 290 (16), 256 (27), 114 (20), 97 (14), 85 (20), 83
(21), 71 (20), 70 (33), 69 (12).
(374 mg, 40%); IR (CHCl3) 1620 cmK1
;
1H NMR
(CDCl3) 3.57–3.61 (m, 4H), 3.67 (s, 3H), 3.68–3.72 (m,
4H), 3.83 (s, 3H), 3.86 (s, 3H), 5.31 (s, 2H), 6.14 (dd, JZ
4.0, 2.8 Hz, 1H), 6.21 (s, 1H), 6.35 (dd, JZ4.0, 1.6 Hz, 1H,
H), 6.78 (dd, JZ2.8, 1.6 Hz, 1H); 13C NMR (CDCl3) 45.6,
55.9, 56.3, 60.7, 60.9, 66.8, 85.6, 107.5, 108.2, 113.0, 124.9,
126.0, 136.3, 141.3, 152.9, 153.8, 162.8. MS (EI) m/z (rel
intensity) 486 (MC, 3), 360 (23), 359 (100), 307 (17), 273
(6), 267 (9), 266 (55), 114 (7), 70 (8).
3.3.25. 1-[3-(2-Iodo-4,5-dimethoxyphenyl)-propyl]-pyr-
role-2-carboxylic acid morpholine amide (14b). Accord-
ing to the general procedure, pyrrole-2-carboxamide 4c
(900 mg, 5 mmol) was treated with KOH (1.22 mg,
20 mmol) in DMSO (20 mL), and mesylate 12b (2.0 g,
5 mmol). After work-up, flash column chromatography
(silicagel, 30% hexane/AcOEt) afforded 14b as a colourless
oil (1.94 g, 86%); IR (CHCl3) 1616 cmK1 1H NMR
;
(CDCl3) 1.85–2.05 (m, 2H), 2.67 (t, JZ7.4 Hz, 2H),
3.61–3.68 (m, 4H), 3.71–3.80 (m, 4H), 3.86 (s, 3H), 3.88
(s, 3H), 4.25 (t, JZ6.3 Hz, 2H), 6.09 (dd, JZ4.0, 2.6 Hz,
1H), 6.31 (dd, JZ4.0, 1.6 Hz, 1H), 6.66 (s, 1H), 6.80 (dd,
JZ2.6, 1.6 Hz, 1H), 7.18 (s, 1H); 13C NMR (CDCl3) 32.3,
37.7, 45.6, 47.6, 55.9, 56.1, 67.1, 87.8, 107.1, 112.0, 113.0,
121.7, 124.1, 125.3, 136.2, 147.9, 149.4, 163.2. MS (EI) m/z
(rel intensity) 484 (MC, 7), 370 (8), 358 (24), 357 (100), 271
(18), 270 (39), 243 (10), 207 (10), 177 (25), 151 (10), 120
(11), 114 (71), 108 (13), 80 (19), 70 (16).
3.3.22. 1-[2-(2-Iodo-4,5-dimethoxyphenyl)ethyl]-pyr-
role-2-carboxylic acid methoxy methyl amide (13a).
According to the general procedure, pyrrole-2-carboxamide
4b (150 mg, 1 mmol) was treated with KOH (220 mg,
4 mmol) in DMSO (10 mL), and tosylate 12a (440 mg,
1 mmol). After work-up, flash column chromatography
(silicagel, 30% hexane/AcOEt) afforded 13a as a colourless
oil (290 mg, 67%); IR (CHCl3) 1620 cmK1 1H NMR
;
(CDCl3) 3.13 (t, JZ6.9 Hz, 2H), 3.33 (s, 3H), 3.68 (s, 3H),
3.72 (s, 3H), 3.83 (s, 3H), 4.46 (t, JZ6.9 Hz, 2H), 6.04 (dd,
JZ4.0, 2.6 Hz, 1H), 6.45 (s, 1H), 6.57 (dd, JZ2.6, 1.8 Hz,
1H), 6.91 (dd, JZ4.0, 1.8 Hz, 1H), 7.19 (s, 1H); 13C NMR
(CDCl3) 33.7, 42.1, 49.2, 55.6, 55.9, 60.8, 87.8, 107.1,
112.7, 116.5, 121.0, 122.1, 127.8, 133.6, 147.9, 148.9,
162.3. MS (EI) m/z (rel intensity) 444 (MC, 1), 317 (54),
286 (10), 257 (100), 230 (10), 191 (15), 164 (6).
3.4. Parham cyclisation reactions. General procedure
Method A. To a solution of iodinated pyrrole-2-carbox-
amides 5–7, 13 or 14 (1 mmol) in dry THF (15 mL), t-BuLi
(2.2 mmol) was added at K78 8C, and the resulting mixture
was stirred at this temperature for 3 h, allowed to reach rt,
and stirred for 4 h. The reaction was quenched by the
addition of sat. NH4Cl (10 mL). Et2O (15 mL) was added,
the organic layer was separated, and the aqueous phase was
extracted with CH2Cl2 (3!15 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo.
Flash column chromatography afforded 8a–g, 15 or 16.
3.3.23. 1-[3-(2-Iodo-4,5-dimethoxyphenyl)-propyl]-pyr-
role-2-carboxylic acid methoxy methyl amide (13b).
According to the general procedure, pyrrole-2-carboxamide
4b (440 mg, 2.8 mmol) was treated with KOH (650 mg,
11.5 mmol) in DMSO (10 mL), and mesylate 12b (1.15 mg,
2.8 mmol). After work-up, flash column chromatography
(silicagel, 50% hexane/AcOEt) afforded 13b as a colourless
Method B. To a solution of iodinated pyrrole-2-carbox-
amides 5–7, 13 or 14 (1 mmol) in dry THF (15 mL), t-BuLi
(2.2 mmol) was added at K78 8C, and the resulting mixture
was stirred at this temperature for 3 h. The reaction was
quenched by the addition of sat. NH4Cl (10 mL). Et2O
(15 mL) was added, the organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3!15 mL). The
combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Flash column chromatography
afforded pyrroloisoquinolones 8a–g, 15 or 16.
oil (1.14 g, 86%); IR (CHCl3) 1622 cmK1 1H NMR
;
(CDCl3) 1.95–2.11 (m, 2H), 2.64 (t, JZ7.4 Hz, 2H), 3.31
(s, 3H), 3.69 (s, 3H), 3.81, 3.84 (s, 3H), 4.38 (t, JZ6.3 Hz,
2H), 6.11 (dd, JZ4.0, 2.6 Hz, 1H), 6.71 (s, 1H), 6.81 (dd,
JZ2.6, 1.8 Hz, 1H), 6.91 (dd, JZ4.0, 1.8 Hz, 1H), 7.19 (s,
1H); 13C NMR (CDCl3) 32.5, 34.0, 37.6, 48.8, 55.9, 56.1,
61.0, 87.9, 107.5, 112.0, 116.5, 121.6, 122.6, 127.3, 136.4,
147.8, 149.3, 162.6. MS (EI) m/z (rel intensity) 458 (MC,
13), 427 (13), 370 (13), 331 (27), 272 (20), 271 (100), 243
(21), 199 (11), 176 (22), 120 (10), 109 (12), 108 (14), 106
(13), 80 (61).
3.4.1. 5H-Pyrrolo[1,2-b]isoquinolin-10-one (8a). Accord-
ing to the general procedure B pyrrole-2-carboxamide 6a
(288 mg, 0.78 mmol) was treated with t-BuLi (1.07 mL of a
1.6 M solution in pentane, 1.72 mmol). After work up, flash
column chromatography (silicagel, 50% hexane/AcOEt)
afforded 8a as a colourless oil (125 mg, 87%); IR (neat)
3.3.24. 1-[2-(2-Iodo-4,5-dimethoxyphenyl)-ethyl]-pyr-
role-2-carboxylic acid morpholine amide (14a). Accord-
ing to the general procedure, pyrrole-2-carboxamide 4c
(480 mg, 2.7 mmol) was treated with KOH (600 mg,
10.7 mmol) in DMSO (10 mL), and tosylate 12a (1.06 g,
2.7 mmol). After work-up, flash column chromatography
(silicagel, 30% hexane/AcOEt) afforded 14a as a colourless
1
1642 cmK1; H NMR (CDCl3) 5.38 (s, 2H), 6.44 (dd, JZ
4.0, 2.4 Hz, 1H), 7.08–7.09 (m, 1H,), 7.20 (dd, JZ4.0,
1.5 Hz, 1H), 7.33 (dd, JZ7.6, 0.9 Hz, 1H), 7.47 (td, JZ7.3,
0.9 Hz, 1H), 7.56 (td, JZ7.3, 1.4 Hz, 1H), 8.30 (dd, JZ7.6,
1.4 Hz, 1H); 13C NMR (CDCl3) 46.9, 111.6, 113.6, 125.6,
127.1, 127.8, 129.6, 130.5, 132.4, 135.6, 174.7. MS (EI) m/z
(rel intensity) 183 (MC, 100), 182 (58), 155 (11), 154 (51),
128 (12), 127 (30), 89 (16), 77 (20), 63 (20), 51 (13). Anal.
Calcd for C12H9NO: C, 78.67; H, 4.95; N, 7.65. Found: C,
78.88; H, 4.82; N, 7.54.
oil (880 mg, 70%); IR (CHCl3) 1618 cmK1 1H NMR
;
(CDCl3) 3.12 (t, JZ6.9 Hz, 2H), 3.69–3.73 (m, 8H), 3.73 (s,
3H), 3.84 (s, 3H), 4.34 (t, JZ6.9 Hz, 2H), 6.03 (dd, JZ4.0,
2.6 Hz, 1H), 6.27 (dd, JZ4.0, 1.6 Hz, 1H), 6.45 (s, 1H),
6.61 (dd, JZ2.6, 1.6 Hz, 1H), 7.18 (s, 1H); 13C NMR
(CDCl3) 42.4, 45.6, 48.0, 55.8, 56.0, 66.9, 87.9, 107.0,
112.8, 113.0, 121.2, 124.0, 125.7, 133.5, 148.1, 149.1,

J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
3321
3.4.2. 7,8-Dimethyl-5H-pyrrolo[1,2-b]isoquinolin-10-one
(8b). According to the general procedure B pyrrole-2-
carboxamide 7b (122 mg, 0.29 mmol) was treated with
t-BuLi (0.72 mL of a 1.05 M solution in pentane,
0.81 mmol). After work up, flash column chromatography
(silicagel, 20% hexane/AcOEt) afforded 8b as a colourless
oil (63 mg, 98%); IR (neat) 1638 cmK1; 1H NMR (CDCl3)
2.35 (s, 6H), 5.33 (s, 2H), 6.43 (dd, JZ4.0, 2.8 Hz, 1H),
7.06 (dd, JZ2.8, 1.6 Hz, 1H), 7.10 (s, 1H), 7.18 (dd, JZ4.0,
1.6 Hz, 1H), 8.06 (s, 1H); 13C NMR (CDCl3) 19.5, 20.1,
46.6, 111.4, 113.2, 125.3, 126.6, 127.6, 128.3, 129.7, 133.2,
136.6, 142.2, 175.1. MS (EI) m/z (rel intensity) 211 (MC,
100), 210 (28), 197 (12), 196 (80), 168 (13), 167 (15). Anal.
Calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C,
79.51; H, 6.17; N, 6.51.
174.2. MS (EI) m/z (rel intensity) 243 (MC, 100), 242 (12),
213 (16), 212 (63), 198 (10), 185 (16), 157 (16). Anal. Calcd
for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.79;
H, 5.48; N, 5.72.
3.4.6. 7,8-Methylenedioxy-5H-pyrrolo[1,2-b]isoquinolin-
10-one (8f). According to the general procedure B pyrrole-
2-carboxamide 6f (159 mg, 0.38 mmol) was treated with
t-BuLi (0.52 mL of a 1.6 M solution in pentane,
0.84 mmol). After work up, flash column chromatography
(silicagel, 30% hexane/AcOEt) afforded 8f as a white
powder, that was crystallised from Et2O (163 mg, 73%):
mp(Et2O) 181–183 8C; IR (KBr) 1640 cmK1 1H NMR
;
(CDCl3) 5.24 (s, 2H), 6.03 (s, 2H), 6.38 (dd, JZ4.0, 2.8 Hz,
1H), 6.69 (s, 1H), 7.02 (broad s, 1H), 7.10 (dd, JZ4.0,
1.2 Hz, 1H), 7.64 (s, 1H); 13C NMR (CDCl3) 46.9, 101.9,
105.0, 105.9, 111.3, 112.9, 125.2, 129.2, 131.7, 147.8,
151.5, 173.8. MS (EI) m/z (rel intensity) 227 (MC, 66), 226
(MCK1, 26), 169 (17), 141 (14), 87 (14), 85 (72), 83 (100).
Anal. Calcd for C13H9NO3: C, 68.72; H, 3.99; N, 6.16.
Found: C, 68.28; H, 3.86; N, 5.94.
3.4.3. 7-Methoxy-5H-pyrrolo[1,2-b]isoquinolin-10-one
(8c). According to the general procedure A pyrrole-2-
carboxamide 7c (261 mg, 0.61 mmol) was treated with
t-BuLi (1.68 mL of a 0.8 M solution in pentane, 1.3 mmol).
After work up, flash column chromatography (silicagel,
50% hexane/AcOEt) afforded 8c as a colourless oil
1
(105 mg, 81%); IR (neat) 1638 cmK1; H NMR (CDCl3)
3.4.7. 7,8,9-Trimethoxy-5H-pyrrolo[1,2-b]isoquinolin-
10-one (8g). According to the general procedure B
pyrrole-2-carboxamide 6g (202 mg, 0.43 mmol) was treated
with t-BuLi (0.59 mL of a 1.6 M solution in pentane,
0.95 mmol). After work up, flash column chromatography
(silicagel, 50% hexane/AcOEt) afforded 8g as a colourless
oil that was crystallised from Et2O (80 mg, 68%): mp(Et2O)
3.88 (s, 3H), 5.34 (s, 2H), 6.41 (dd, JZ4.0, 2.4 Hz, 1H),
6.78 (dd, JZ2.4, 1.2 Hz, 1H), 6.98 (dd, JZ8.7, 2.4 Hz, 1H),
7.04 (dd, JZ2.4, 1.6 Hz, 1H), 7.16 (dd, JZ4.0, 1.2 Hz, 1H),
8.25 (d, JZ8.7 Hz, 1H); 13C NMR (CDCl3) 47.0, 55.5,
110.1, 111.4, 113.1, 114.0, 123.9, 125.2, 129.4, 129.6,
137.9, 162.8, 174.3. MS (EI) m/z (rel intensity) 213 (MC,
100), 182 (24), 170 (41), 169 (14), 142 (13), 141 (13), 115
(10), 87 (14), 85 (66), 83 (94). Anal. Calcd for C13H11NO2:
C, 73.22; H, 5.20; N, 6.57. Found: C, 73.14; H, 5.27; N,
6.41.
1
144–145 8C; IR (neat) 1639 cmK1; H NMR (CDCl3) 3.91
(s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 5.30 (s, 2H), 6.38 (dd, JZ
4.0, 2.4 Hz, 1H), 6.60 (s, 1H), 6.97 (dd, JZ2.4, 1.6 Hz, 1H),
7.10 (dd, JZ4.0, 1.6 Hz, 1H); 13C NMR (CDCl3) 47.0, 56.0,
61.2, 61.7, 104.3, 111.1, 112.7, 118.4, 124.0, 130.4, 133.8,
142.6, 155.5, 156.6, 174.0. MS (EI) m/z (rel intensity) 273
(MC, 76), 272 (6), 259 (14), 258 (100), 256 (12), 240 (9),
230 (11), 228 (8), 227 (14), 215 (17), 213 (6), 212 (14), 207
(9), 198 (8), 197 (6), 184 (6), 170 (6), 137 (17), 94 (15), 85
(7), 83 (8), 51 (7). Anal. Calcd for C15H15NO4: C, 65.92; H,
5.53; N, 5.12. Found: C, 66.17; H, 5.65; N, 5.12.
3.4.4. 7,8-Dimethoxy-5H-pyrrolo[1,2-b]isoquinolin-10-
one (8d). According to the general procedure B pyrrole-2-
carboxamide 7d (425 mg, 0.93 mmol) was treated with
t-BuLi (2.0 mL of a 1.3 M solution in pentane, 2.61 mmol).
After work up, flash column chromatography (silicagel,
50% hexane/AcOEt) afforded 8d as a colourless oil
1
(199 mg, 88%); IR (neat) 1650 cmK1; H NMR (CDCl3)
3.90 (s, 3H), 3.92 (s, 3H), 5.17 (s, 2H), 6.35 (dd, JZ4.0,
2.4 Hz, 1H), 6.64 (s, 1H), 6.95–6.97 (m, 1H), 7.08 (dd, JZ
4.0, 1.5 Hz, 1H), 7.63 (s, 1H); 13C NMR (CDCl3) 46.4, 56.0,
56.0, 107.1, 107.9, 111.1, 112.7, 123.7, 125.2, 129.2, 129.7,
148.7, 152.8, 174.1. MS (EI) m/z (rel intensity) 243 (MC,
100), 242 (22), 228 (21), 212 (28), 200 (13), 199 (13). Anal.
Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C,
69.24; H, 5.41; N, 5.84.
3.4.8. 8,9-Dimethoxy-5,6-dihydropyrrolo[1,2-a]benzo-
[d]azepin-11-one (15). According to the general procedure
B pyrrole-2-carboxamide 14a (108 mg, 0.23 mmol) was
treated with t-BuLi (0.57 mL of a 1.0 M solution in pentane,
0.57 mmol). After work up, flash column chromatography
(silicagel, 50% hexane/AcOEt) afforded 15 as a colourless
oil that was crystallised from pentane (23 mg, 58%): mp
(pentane) 122–124 8C; IR (neat) 1639 cmK1 1H NMR
;
(CDCl3) 3.24–3.28 (m, 2H), 3.93 (s, 6H), 4.30–4.34 (m,
2H), 6.20 (dd, JZ4.0, 2.4 Hz, 1H), 6.63 (s, 1H), 6.82 (dd,
JZ2.4, 2.0 Hz, 1H), 7.36 (dd, JZ4.0, 2.0 Hz, 1H), 7.75 (s,
1H); 13C NMR (CDCl3) 35.6, 50.0, 56.0, 109.4, 111.7,
113.6, 121.0, 127.9, 129.5, 133.5, 133.6, 147.9, 151.9,
179.4. MS (EI) m/z (rel intensity) 258 (MC C1; 18), 257
(MC, 100), 256 (15), 242 (10), 191 (35), 164 (12). Anal.
Calcd for C15H15NO3: C, 70.02; H, 5.87; N, 5.44. Found: C,
69.98; H, 5.43; N, 5.37.
3.4.5. 6,7-Dimethoxy-5H-pyrrolo[1,2-b]isoquinolin-10-
one (8e). According to the general procedure B pyrrole-2-
carboxamide 7e (140 mg, 0.31 mmol) was treated with
t-BuLi (0.77 mL of a 1.12 M solution in pentane,
0.86 mmol). After work up, flash column chromatography
(silicagel, 20% hexane/AcOEt) afforded 8e as a white
powder, that was crystallised from Et2O (53 mg, 76%):
mp(Et2O) 177–179 8C; IR (KBr) 1640 cmK1 1H NMR
;
(CDCl3) 3.94 (s, 3H), 3.97 (s, 3H), 5.37 (s, 2H), 6.43 (dd,
JZ4.0, 2.4 Hz, 1H), 7.05 (d, JZ8.7 Hz, 1H), 7.10 (dd, JZ
2.4, 1.6 Hz, 1H), 7.17 (dd, JZ4.0, 1.6 Hz, 1H), 8.09 (d, JZ
8.7 Hz, 1H); 13C NMR (CDCl3) 43.4, 55.9, 60.3, 111.5,
113.1, 123.9, 124.1, 125.7, 129.3, 129.9, 143.8, 155.6,
3.4.9. 9,10-Dimethoxy-6,7-dihydro-5H-pyrrolo[1,2-a]-
benzo[d]azocin-12-one (16). According to the general
procedure B pyrrole-2-carboxamide 13b (269 mg,
0.59 mmol) was treated with t-BuLi (1.36 mL of a 1.08 M

3322
J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
solution in pentane, 1.47 mmol). After work up, flash
column chromatography (silicagel, 40% hexane/AcOEt)
afforded 16 as a colourless oil (88 mg, 55%); IR (neat)
0.8 mmol); IR (neat) 1618 cmK1; 1H NMR (CDCl3) 1.03 (t,
JZ7.1 Hz, 6H), 3.34 (q, JZ7.1 Hz, 4H), 3.78 (s, 3H), 3.81
(s, 3H), 5.22 (s, 2H), 6.07 (dd, JZ3.6, 2.8 Hz, 1H), 6.31 (dd,
JZ3.6, 1.6 Hz, 1H), 6.62–6.66 (m, 2H), 6.72–6.75 (m, 1H),
6.78 (dd, JZ2.8, 1.6 Hz, 1H); 13C NMR (CDCl3) 13.3, 42.0,
51.3, 55.7, 55.8, 106.6, 110.5, 110.9, 119.6, 124.7, 125.8,
131.1, 148.2, 148.8, 163.9. MS (EI) m/z (rel intensity) 316
(MC, 18), 244 (6), 243 (18), 216 (8), 152 (12), 151 (100),
107 (11), 72 (9). Anal. Calcd for C18H24N2O3: C, 68.33; H,
7.64; N, 8.85. Found: C, 68.54; H, 7.46; N, 8.77.
1
1590 cmK1; H NMR (CDCl3) 1.85–2.01 (m, 2H), 2.66 (t,
JZ7.4 Hz, 2H), 3.31 (s, 3H), 3.69 (s, 3H), 3.81, 3.84 (s, 3H),
4.38 (t, JZ6.3 Hz, 2H), 6.22 (dd, JZ4.0, 2.6 Hz, 1H), 6.57
(s, 1H), 6.76 (dd, JZ2.6, 1.8 Hz, 1H), 7.24 (dd, JZ4.0,
1.8 Hz, 1H), 7.31 (s, 1H); 13C NMR (CDCl3) 29.6, 32.8,
45.6, 55.9, 109.4, 111.1, 112.6, 119.3, 128.0, 131.2, 132.4,
135.7, 147.6, 152,0, 183.1. MS (EI) m/z (rel intensity) 271
(MC, 100), 254 (10), 243 (27), 242 (15), 228 (17), 212 (17),
191 (30), 163 (12), 106 (12). Anal. Calcd for C16H17NO3: C,
70.83; H, 6.31; N, 5.16. Found: C, 70.53; H, 6.20; N, 5.22.
3.4.14. 1-(2,3-Dimethoxybenzyl)pyrrole-2-carboxylic
acid diethyl amide (9e). Obtained as a by-product
(41 mg, 35%) when, according to the general procedure
A, pyrrole-2-carboxamide 5e (162 mg, 0.4 mmol) was
treated with t-BuLi (0.5 mL of a 1.6 M solution in pentane,
0.8 mmol); IR (neat) 1618 cmK1; 1H NMR (CDCl3) 1.09 (t,
JZ7.1 Hz, 6H), 3.42 (q, JZ7.1 Hz, 4H), 3.76 (s, 3H), 3.83
(s, 3H), 5.34 (s, 2H), 6.07 (dd, JZ4.0, 2.8 Hz, 1H), 6.31 (dd,
JZ4.0, 1.6 Hz, 1H), 6.52 (d, JZ7.9 Hz, 1H), 6.79 (dd, JZ
2.8, 1.6 Hz, 1H), 6.82 (s, 1H), 6.93 (t, JZ7.9 Hz, 1H); 13C
NMR (CDCl3) 13.4, 46.5, 55.7, 60.4, 106.6, 110.8, 111.7,
120.7, 123.8, 125.2, 126.0, 132.3, 146.6, 152.4, 164.0. MS
(EI) m/z (rel intensity) 316 (MC, 56), 285 (21), 245 (10),
244 (57), 243 (15), 229 (10), 228 (39), 216 (16), 214 (17),
212 (16), 186 (13), 165 (10), 152 (11), 151 (76), 137 (13),
136 (100), 135 (11), 122 (16), 106 (13), 100 (13), 94 (14), 91
(58), 80 (11), 78 (11), 77 (11), 72 (29), 65 (22).
3.4.10. 1-Benzylpyrrole-2-carboxylic acid diethyl amide
(9a). Obtained as a by-product (14 mg, 13%) when,
according to the general procedure A, pyrrole-2-carbox-
amide 5a (160 mg, 0.4 mmol) was treated with t-BuLi
(0.6 mL of a 1.6 M solution in pentane, 0.9 mmol); IR (neat)
1618 cmK1; 1H NMR (CDCl3) 1.02 (t, JZ7.1 Hz, 6H), 3.32
(q, JZ7.1 Hz, 4H), 5.31 (s, 1H), 6.10 (dd, JZ3.6, 2.4 Hz,
1H), 6.33 (dd, JZ3.6, 1.6 Hz, 1H), 6.81 (dd, JZ2.4, 1.6 Hz,
1H), 7.06–7.10 (m, 2H), 7.17–7.29 (m, 3H); 13C NMR
(CDCl3) 13.5, 42.1, 51.5, 106.6, 111.1, 124.9, 125.9, 127.1,
127.3, 128.3, 138.5, 163.8. MS (EI) m/z (rel intensity) 256
(MC, 15), 184 (38), 183 (14), 156 (25), 91 (100), 72 (16), 65
(26).
3.4.11. 1-(3,4-Dimethylbenzyl)pyrrole-2-carboxylic acid
diethyl amide (9b). Obtained as a by-product (10 mg, 18%)
when, according to the general procedure A, pyrrole-2-
carboxamide 5b (80 mg, 0.2 mmol) was treated with t-BuLi
(0.4 mL of a 1.0 M solution in pentane, 0.4 mmol); IR (neat)
1618 cmK1; 1H NMR (CDCl3) 1.04 (t, JZ7.1 Hz, 6H), 2.19
(s, 3H), 2.20 (s, 3H), 3.35 (q, JZ7.1 Hz, 4H), 5.23 (s, 2H),
6.08 (dd, JZ4.0, 2.8 Hz, 1H), 6.32 (dd, JZ4.0, 1.6 Hz, 1H),
6.78–6.84 (m, 2H), 6.89 (s, 1H), 7.01 (d, JZ8.0 Hz, 1H);
13C NMR (CDCl3) 13.3, 19.4, 19.7, 41.4, 51.3, 106.6, 111.0,
124.8, 125.9, 128.7, 129.6, 135.6, 135.9, 136.5, 164.0. MS
(EI) m/z (rel intensity) 284 (MC, 18), 212 (25), 211 (24),
196 (16), 184 (21), 120 (12), 119 (100), 91 (23), 77 (11), 72
(20).
3.4.15. 1-(3,4-Methylendioxybenzyl)pyrrole-2-car-
boxylic acid diethyl amide (9f). Obtained as a by-product
(11 mg, 14%) when, according to the general procedure A,
pyrrole-2-carboxamide 5f (112 mg, 0.3 mmol) was treated
with t-BuLi (0.4 mL of a 1.6 M solution in pentane,
0.6 mmol); 1H NMR (CDCl3) 1.08 (t, JZ7.1 Hz, 6H),
3.37 (q, JZ7.1 Hz, 4H), 5.20 (s, 2H), 5.90 (s, 2H), 6.08 (dd,
JZ4.0, 2.4 Hz, 1H), 6.32 (dd, JZ4.0, 1.6 Hz, 1H), 6.61–
6.69 (m, 2H), 6.71–6.74 (m, 1H), 6.78 (dd, JZ2.4, 1.6 Hz,
1H).
3.4.16. 1-(3,4,5-Trimethoxybenzyl)pyrrole-2-carboxylic
acid diethyl amide (9g). According to the general
procedure
A
pyrrole-2-carboxamide 5g (140 mg,
3.4.12. 1-(3-Methoxybenzyl)pyrrole-2-carboxylic acid
diethyl amide (9c). Obtained as a by-product (13 mg,
39%) when, according to the general procedure A, pyrrole-
2-carboxamide 5c (48 mg, 0.1 mmol) was treated with
t-BuLi (0.2 mL of a 1.0 M solution in pentane, 0.2 mmol);
IR (neat) 1604 cmK1; 1H NMR (CDCl3) 1.04 (t, JZ7.1 Hz,
6H), 3.35 (c, JZ7.1 Hz, 4H), 3.74 (s, 3H), 5.28 (s, 2H), 6.10
(dd, JZ3.6, 2.8 Hz, 1H), 6.33 (dd, JZ3.6, 1.6 Hz, 1H),
6.62–6.80 (m, 4H), 7.17 (t, JZ7.9 Hz, 1H); 13C NMR
(CDCl3) 13.3, 40.5, 51.5, 55.1, 106.8, 111.2, 112.7, 112.8,
119.4, 125.0, 126.0, 129.4, 140.2, 159.7, 163.9 (CO). MS
(EI) m/z (rel intensity) 286 (MC, 61), 215 (16), 214 (86),
213 (51), 187 (26), 186 (41), 170 (11), 122 (15), 121 (100),
94 (10), 91 (34), 78 (18), 77 (16), 72 (24), 65 (12).
0.3 mmol) was treated with t-BuLi (0.7 mL of a 1.0 M
solution in pentane, 0.7 mmol). After work up, flash column
chromatography (silicagel, 50% hexane/AcOEt) afforded 9g
as a colourless oil (83 mg, 81%); IR (neat) 1616 cmK1; 1H
NMR (CDCl3) 1.02 (t, JZ7.1 Hz, 6H), 3.35 (q, JZ7.1 Hz,
4H), 3.75 (s, 6H), 3.77 (s, 3H), 5.24 (s, 2H), 6.09 (dd, JZ
3.6, 2.8 Hz, 1H), 6.29 (s, 2H), 6.33 (dd, JZ3.6, 1.6 Hz, 1H),
6.80 (dd, JZ2.4, 1.6 Hz, 1H); 13C NMR (CDCl3) 13.3, 40.9,
51.7, 55.9, 60.7, 104.0, 106.7, 111.4, 125.0, 125.8, 134.3,
153.1, 163.7. MS (EI) m/z (rel intensity) 346 (MC, 39), 273
(11), 242 (38), 182 (16), 181 (100), 137 (11), 83 (14).
Acknowledgements
3.4.13. 1-(3,4-Dimethoxybenzyl)pyrrole-2-carboxylic
acid diethyl amide (9d). Obtained as a by-product
(30 mg, 24%) when, according to the general procedure
A, pyrrole-2-carboxamide 5d (176 mg, 0.4 mmol) was
treated with t-BuLi (0.5 mL of a 1.6 M solution in pentane,
Financial support from MCYT (BQU2003-03239), and
´
Universidad del Paıs Vasco/Euskal Herriko Unibertsitatea is
gratefully acknowledged. We also thank MEC and
UPV/EHU for grants (J.R. & R.I.).

J. Ruiz et al. / Tetrahedron 61 (2005) 3311–3324
3323
15. Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3,
2177–2179.
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