Synthesis of pyrrolo[1,2-b]isoquinolines through mesityllithium-mediated intramolecular carbolithiation

Article abstract of DOI:10.1055/s-0028-1087411

Mesityllithium has proven to be an effective iodine-lithium exchange reagent. Thus, carbolithiation reactions on 2-alkenyl-substituted N-(o-iodobenzyl)pyrroles have been accomplished avoiding side reactions to afford pyrroloisoquinolines in high yields (8

Full text of DOI:10.1055/s-0028-1087411

3188
LETTER
Synthesis of Pyrrolo[1,2-b]isoquinolines through Mesityllithium-Mediated
Intramolecular Carbolithiation
I
ntramolecular
e
Carbolithi
r
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea,
Apdo. 644, 48080 Bilbao, Spain
E-mail: esther.lete@ehu.es
Received 5 August 2008
via a diastereoselective carbolithiation of chiral 2-(o-bromo-
Abstract: Mesityllithium has proven to be an effective iodine–lith-
phenyl)-substituted perhydro-1,3-benzoxazines, derived from
(–)-8-aminomenthol is the only example of 6-exo cycliza-
tion process.
Therefore, in connection with our previous studies,14 we
decided to investigate the intramolecular carbolithiation
of 2-alkenyl-substituted N-(o-iodobenzyl)pyrroles 3, us-
ing alkenes with different substitution patterns as internal
electrophiles for the synthesis of pyrrolo[1,2-b]isoquino-
lines 4 (Scheme 1).
ium exchange reagent. Thus, carbolithiation reactions on 2-alkenyl-
substituted N-(o-iodobenzyl)pyrroles have been accomplished
avoiding side reactions to afford pyrroloisoquinolines in high yields
(80–92%), improving the results obtained with t-BuLi. The carbo-
lithiation reaction requires the use of electron-deficient alkenes.
Mesityllithium has also been studied as an alternative to t-BuLi in
Parham cyclization with other internal electrophiles (aldehyde, ke-
tone, ester, amide), proving to be more selective and efficient than
t-BuLi.
Key words: organolithium, carbanions, carbolithiation, metalation,
heterocycles
CHO
(5a)
MeO
MeO
I
MeO
MeO
I
N
H
The synthetic utility of lithium–halogen exchange
reaction1 for the metalation of aromatic substrates, though
mechanistically controversial,2 have been shown in the
facile construction of benzo-fused cyclic ring systems via
intramolecular reaction of the so-generated aryllithium
compounds with internal electrophiles,3 a metalation–
cyclization process known as Parham cyclization.4,5
N
Br
KOH, DMSO
r.t., 4 h
CHO
1
2a 89%
CH2Cl2
reflux, 4 d
Ph3P=CHR
MeO
R
I
MeO
t-BuLi (Table 1)
On the other hand, the intramolecular carbolithiation6 of
olefinic organolithiums is rapidly growing in popularity
as a preparative method for cyclopentylmethyllithiums
and their heterocyclic analogues. The attraction of this
methodology lies in the high regio- and stereoselectivity
when carbon–carbon bond is formed and in the possibility
of trapping the resulting cyclized organolithium with var-
ious electrophiles to introduce diverse functionality into
the cyclized products. Although many of these carbolithi-
ations involve alkyl- or alkenyllithiums,7there are also
some examples of cycloisomerization of alkenyl-substi-
tuted aryllithiums generated by metal–halogen exchange.
Thus, intramolecular carbolithiation reaction of unsaturat-
ed aryllithiums is particularly well suited for the construc-
tion of five-membered rings through a 5-exo-trig
cyclization process, as it has been shown in the synthesis
of carbocyclic8 and heterocyclic compounds,9 even in a
diastereoselective10 or enantioselective fashion.11,12 How-
ever, intramolecular carbolithiation reactions have only
been scarcely applied to the synthesis of six-membered
rings. To our knowledge, the synthesis of enantiopure 4-
substituted tetrahydroisoquinolines achieved by Pedrosa13
or
N
N
R
MesLi (Table 2)
MeO
MeO
4a R = H
4b R = CBz
3a R = H 80%
4c R = CONEt2
4d R = COt-Bu
3b R = CBz 85%
3c R = CONEt2 97%
Scheme 1 Synthesis and carbolithiation reactions of 3a–c
The synthetic starting point was the N-benzylpyrrole-2-
carbaldehyde 2a, which was prepared by alkylation of
commercially available pyrrole-2-carbaldehyde 5a with
the 2-iodo-4,5-dimethoxybenzyl bromide (1)14b using a
standard procedure. The olefination of aldehyde 2a was
achieved via Wittig reaction with the corresponding phos-
phorus ylides to afford 2-vinyl-substituted N-(o-iodoben-
zyl)pyrroles 3a–c in good overall yields (Scheme 1).
We first studied the carbolithiation reactions of N-(o-iodo-
benzyl)pyrroles 3a–c with t-BuLi and TMEDA
(Scheme 1, Table 1), starting from previously used condi-
tions.10a However, although iodine–lithium exchange oc-
curred efficiently, addition of t-BuLi to the unsubstituted
alkene in 3a was competitive with cyclization, isolating 7
and 6 (Table 1, entry 1). The use of equimolecular
amounts of t-BuLi and TMEDA resulted in a low conver-
SYNLETT 2008, No. 20, pp 3188–3192
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087411; Art ID: D29208ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Intramolecular Carbolithiation
3189
Table 1 Carbolithiation Reactions of 3a–c with tert-Butyllithium
tries 8 and 10), although variable amounts of 8b (10–16%)
were isolated.
Entry Substrate t-BuLi TMEDA Temp
Product Yield
(%)
In order to avoid these side reactions in the intramolecular
carbolithiation of 3a–c, we decided to study the possibili-
ty of using a more bulky and less nucleophilic reagent for
the iodine–lithium exchange reaction. In this context,
mesityllithium (MesLi) has been described to be a strong-
ly basic, non-nucleophilic and selective reagent.15 Mesi-
tyllithium has been used in organic synthesis mainly as an
LDA equivalent, for deprotonation reactions,16 and there
are only a few examples of its use in aromatic metalation17
or in halogen–lithium exchange reactions.18
(equiv) (equiv) (°C)
a
1
2
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
2
1
2
2
1
2
2
1
1
1
2
1
2
–
–
–
2
1
–
1
–78 to 0
–78 to 0
–78 to 0
–78
–
–
–
–
b
c
–
3
–
4
4bd
4bd
4bd
4ce
4c
39
38
42
27
39
41
31
5
–78
6
–90
Thus, as shown in Table 2, lithium–iodine exchange was
performed efficiently with MesLi, although the unsubsti-
tuted alkene 3a was also unreactive under these conditions
(entry 1), isolating the non-iodinated benzylpyrrole 6, but
avoiding the direct addition of the organolithium reagent
to the alkene. At higher temperatures (–20 or 0 °C, entries
2 and 3), decomposition of the aryllithium intermediate
was observed. On the other hand, we were pleased to find
that cyclization of 3b and 3c took place smoothly at low
temperature and in only 5 minutes to afford pyrroloiso-
quinolines 4b,c in high yields and avoiding side reactions
(entries 4–7).19
7
–78
8
–78
9
–78
4c
10
–105
4c
a De-iodinated benzylpyrrole 6 (26%) and addition product 7 (49%)
were isolated.
b Compound 6 (17%) was isolated.
c Addition product 8a (22%) was isolated.
d Addition product 4d (20–25%) was also isolated.
e Addition product 8b (24%) was also isolated.
Table 2 Carbolithiation Reactions of 3a–c with Mesityllithium
R
t-Bu
Entry
Substrate Temp (°C) Time
Product Yield (%)
t-Bu
Ar
Ar
N
Ar
N
N
1
2
3
4
5
6
7
3a
3a
3a
3b
3b
3c
3c
–78
–20
0
4 h
20 h
3 h
6
42
16
–
6
7
8a R = COt-Bu
8b R = CONEt2
6
Ar = 3,4-(MeO)2C6H3
–
Figure 1 Byproducts from t-BuLi-mediated carbolithiation of 3a–c
–78
–105
–78
–105
5 min
4b
4b
4c
4c
80
92
83
90
sion, and the isolation of de-iodinated 6 (Figure 1), to-
gether with unreacted starting material.
5 min
5 min
5 min
Therefore, we studied the carbolithiation reactions on 3b,
where the alkene was substituted with an electron-with-
drawing group (CO2Bn). However, under standard condi-
tions (Table 1, entry 3), the direct addition of t-BuLi to
both the alkene and the ester moieties was competitive in
the presence of TMEDA, yielding a mixture of products
where only 8a was isolated. Although cyclization took
place in the absence of TMEDA (entries 4–6), the addition
of t-BuLi to the ester moiety could not be avoided under
various conditions, isolating pyrroloisoquinoline 4d as a
byproduct, together with 4b, in all cases. Therefore, we
tested the possibility of using an amide as electron-with-
drawing group (3c, R = CONEt2). Thus, when the reaction
was carried out in the presence of TMEDA (entry 7), pyr-
roloisoquinoline 4c was obtained, although in low yield,
due to competitive direct conjugate addition of t-BuLi to
afford 8b. The yield of 4c could be slightly improved in
the absence of TMEDA (entry 9) or lowering the temper-
ature or the number of equivalents of organolithium (en-
In view of these results, we decided to compare the effi-
ciency of MesLi with t-BuLi in this type of reaction using
other internal electrophiles. In this context, Kondo had al-
ready established the compatibility of MesLi with keto-
esters in Parham cyclization.18 For this purpose, we pre-
pared benzylpyrroles 2b–f by a standard procedure,20
which bear different types of carbonyl groups (aldehyde,
ketone, ester, and amide) as internal electrophiles.
We first tried the Parham cyclization with 2a, using an al-
dehyde as internal electrophile. However, as it could be
expected, the aldehyde carbonyl was too reactive under
the conditions tested (Scheme 2, Table 3, entries 1–3),
and only addition of MesLi to the carbonyl group was ob-
served (compound 10, Figure 2), besides iodine–lithium
exchange. For this reason, the reaction was not tried with
t-BuLi.
Synlett 2008, No. 20, 3188–3192 © Thieme Stuttgart · New York

3190
S. Lage et al.
LETTER
HO
R
amides behave as excellent internal electrophiles in
Parham cyclizations with t-BuLi.14 As shown in entries 4–
7 (Table 4), MesLi behaves as a more effective metalating
agent, improving the yield of 12 and shortening the reac-
tion times.
MeO
MeO
I
MeO
MeO
RLi
N
N
(see Table 3)
2a–c
O
R
9a–c
a R = H; b R = Me; c R = Ph
O
MeO
MeO
I
MeO
MeO
Scheme 2 Parham cyclization of 2-acylpyrroles 2a–c
Table 3 Parham Cyclization of 2-Acylpyrroles 2a–c
RLi
N
O
N
(see Table 4)
2d R = OMe
2e R = NEt2
2f R = NMe(OMe)
R
Entry Substrate RLi
Temp
(°C)
Time Product Yield
12
(min)
(%)
Scheme 3 Parham cyclization of 2-acylpyrroles 2d–f
Table 4 Parham Cyclization of 2-Acylpyrroles 2d–f
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2b
2b
2c
2c
2c
MesLi
MesLi
MesLi
MesLi
MesLi
t-BuLi
MesLi
MesLi
t-BuLi
–78
–78
60
5
10
9
10
12
6
–105
–78
5
10
Entry Substrate RLi
Temp
(°C)
Time
(min)
Product Yield
(%)
5
11b
11b
11b
9c
23
25
14
95
95
95
1
2
3
4
5
6
7
2d
2d
2d
2e
2e
2f
t-BuLi
MesLi
MesLi
MesLi
t-BuLi
MesLi
t-BuLi
–90
–78
–105
–78
–78
–78
–78
120
5
11d
12
12
12
12
12
12
37
54
69
79
79a
95
86a
–105
–90
5
5
5
–78
5
5
–105
–105
5
9c
180
5
5
9c
Ar
O
2f
180
HO
MeO
MeO
R
a Results previously described in ref. 14b.
N
N
MeO
MeO
In summary, it has been shown that MesLi behaves as an
excellent reagent for lithium–iodine exchange reactions,
avoiding direct addition to the electrophilic group, and
improving the results obtained with t-BuLi. Thus,
pyrroloisoquinolines 4 have been prepared through
MesLi-mediated intramolecular carbolithiation reactions
via a 6-exo cyclization process, though the alkene is re-
quired to be substituted with an electron-withdrawing
group. Furthermore, MesLi improves the results obtained
with t-BuLi in the Parham cyclization with different inter-
nal electrophiles allowing the efficient construction of the
pyrroloisoquinoline nucleus. While Kondo has reported
the application of this type of cyclization to haloaraomat-
ics having alkoxycarbonyl groups using MesLi,18 only a
few successful examples with esters22 or ketones23 have
been described with the usual organolithiums (t-BuLi,
n-BuLi), due to their high reactivity towards the internal
electrophile. As we have shown for the synthesis of pyr-
roloisoquinolines, the use of MesLi could be an interest-
ing alternative for these metalation reactions.
10
11b R = Me
11d R = OMe
Ar = Mes
Figure 2 Byproducts from Parham cyclization of 2a–f
The reaction with an enolizable ketone such as 2b also
failed both with t-BuLi and MesLi (Table 3, entries 4–6).
In this case, no addition product could be isolated but, al-
though the metalation took place, no cyclization was ob-
served, isolating 11b in low yields. Probably, competitive
a-deprotonation of the ketone precludes cyclization.21
Thus, cyclization with nonenolizable ketone 2c took place
in high yield in just 5 minutes both with t-BuLi and MesLi
(Table 3, entries 7–9). On the other hand, MesLi proved to
be more selective than t-BuLi when an ester (2d) was used
as electrophile (Scheme 3, Table 4). Thus, when 2d was
treated with t-BuLi at –90 °C, no cyclization product was
observed, isolating only a moderate yield of noniodinated
benzylpyrrole 11d, together with unreacted 2d (30%,
Table 4, entry 1). A GC-MS analysis of the crude reaction
mixture showed also minor amounts of the corresponding
tert-butyl ketone, result of t-BuLi addition to the carbonyl.
When the reaction was carried out with MesLi, pyrrolo-
isoquinoline 12 was obtained in moderate yield (54%, en-
try 2), which was improved working at lower temperature
(69%, entry 3). Finally, we had previously shown that
Acknowledgment
Financial support from MEC (CTQ2006-01903), Gobierno Vasco
(GIC07/92-IT-227-07), and UPV/EHU is gratefully acknowledged.
Synlett 2008, No. 20, 3188–3192 © Thieme Stuttgart · New York

LETTER
Intramolecular Carbolithiation
3191
(9) For some representative examples on indoles, see:
References and Notes
(a) Barluenga, J.; Sanz, R.; Granados, A.; Fañanás, F. J.
J. Am. Chem. Soc. 1998, 120, 4865. On indolines, see:
(b) Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61,
2596. (c) Zhang, D.; Liebskind, L. J. Org. Chem. 1996, 61,
2594. On azaindolines, see: (d) Bailey, W. F.; Salgaonkar,
P. D.; Brubaker, J. D.; Sharma, V. Org. Lett. 2008, 10, 1071.
(10) (a) Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett.
2002, 4, 791. (b) Fresigné, C.; Girard, A.-L.; Durandetti, M.;
Maddaluno, J. Angew. Chem. Int. Ed. 2008, 41, 891.
(c) Fresigné, C.; Girard, A.-L.; Durandetti, M.; Maddaluno,
J. Chem. Eur. J. 2008, 14, 5159.
(11) (a) Comins, D. L.; Zhang, Y.-M. J. Am. Chem. Soc. 1996,
118, 12248. (b) Nishiyama, H.; Sakata, N.; Sugimoto, H.;
Motoyama, Y.; Wakita, H.; Nagase, H. Synlett 1998, 930.
(12) (a) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122,
6787. (b) Sanz, G.; Groth, U. M. J. Am. Chem. Soc. 2000,
122, 6789. (c) Barluenga, J.; Fañanás, F. J.; Sanz, R.;
Marcos, C. Org. Lett. 2002, 4, 2225. (d) Mealy, M. J.;
Luderer, M. R.; Bailey, W. F.; Sommer, M. B. J. Org. Chem.
2004, 69, 6042. (e) Barluenga, J.; Fañanás, F. J.; Sanz, R.;
Marcos, C. Chem. Eur. J. 2005, 11, 5397. (f) Groth, U.;
Koettgen, P.; Langenbach, P.; Lindenmaier, A.; Schuetz, T.;
Wiegand, M. Synlett 2008, 1301.
(1) (a) Wakefield, B. J. The Chemistry of Organolithium
Compounds, 2nd ed.; Pergamon: New York, 1990.
(b) Rappoport, Z.; Marek, I. The Chemistry of
Organolithium Compounds, Vol. 1; Rappoport, Z., Ed.;
Wiley: Chichester, 2004. (c) Gribble, G. W. In Science of
Synthesis, Vol. 8a; Majewski, M.; Snieckus, V., Eds.;
Thieme: Stuttgart, 2006, 357–426.
(2) Bailey, W. F.; Ovaska, T. V. In Advances in Detailed
Reaction Mechanisms: Mechanisms of Importance in
Synthesis, Vol. 3; Coxon, J. M., Ed.; JAI Press: Greenwich,
1994, 251–273.
(3) For reviews, see (a) Parham, W. E.; Bradsher, C. K. Acc.
Chem. Res. 1982, 15, 300. (b) Gray, M.; Tinkl, M.;
Snieckus, V. In Comprehensive Organometallic Chemistry
II, Vol. 11; Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.;
Pergamon: Exeter, 1995, 66–92. (c) Ardeo, A.; Collado,
M. I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets
in Heterocyclic Systems, Vol. 5; Atanassi, O.; Spinelli, D.,
Eds.; Italian Society of Chemistry: Rome, 2001, 393–418.
(d) Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275.
(e) Nájera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003,
59, 9255; see also ref. 1.
(4) Parham, W. E.; Jones, L. D.; Sayed, Y. A. J. Org. Chem.
1975, 40, 2394; see also ref. 3a.
(13) Pedrosa, R.; Andrés, C.; Iglesias, J. M.; Pérez-Encabo, A.
J. Am. Chem. Soc. 2001, 123, 1817.
(5) For representative examples of our synthetic work in this
area, see: (a) Lete, E.; Egiarte, A.; Sotomayor, N.; Vicente,
T.; Villa, M. J. Synlett 1993, 41. (b) Collado, M. I.;
Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E. J. Org.
Chem. 1997, 62, 2080. (c) Osante, I.; Collado, M. I.; Lete,
E.; Sotomayor, N. Eur. J. Org. Chem. 2001, 1267.
(d) González-Temprano, I.; Sotomayor, N.; Lete, E. Synlett
2002, 593. (e) Osante, I.; Lete, E.; Sotomayor, N.
Tetrahedron Lett. 2004, 45, 1253. (f) González-Temprano,
I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004,
69, 3875. (g) Osante, I.; Sotomayor, N.; Lete, E. Lett. Org.
Chem. 2004, 1, 148. (h) Abdullah, M. N.; Arrassate, S.;
Lete, E.; Sotomayor, N. Tetrahedron 2007, 64, 1329.
(6) For reviews, see: (a) Marek, I. J. Chem. Soc., Perkin Trans.
1 1999, 535. (b) Mealy, M. J.; Bailey, W. F. J. Organomet.
Chem. 2002, 646, 59. (c) Clayden, J. Organolithiums:
Selectivity for Synthesis; Pergamon: New York, 2002, 282–
335. (d) Normant, J. F. Top. Organomet. Chem. 2003, 287.
(e) Fañanás, F. J.; Sanz, R. In The Chemistry of
(14) (a) Ruiz, J.; Sotomayor, N.; Lete, E. Org. Lett. 2003, 5,
1115. (b) Ruiz, J.; Ardeo, A.; Ignacio, R.; Sotomayor, N.;
Lete, E. Tetrahedron 2005, 61, 3311. (c) Ruiz, J.;
Sotomayor, N.; Lete, E. Tetrahedron 2006, 62, 6182.
(15) Mhaske, S. B. Synlett 2005, 184.
(16) (a) Beck, A. K.; Hoekstra, M. S.; Seebach, D. Tetrahedron
Lett. 1977, 18, 1187. (b) Yoshifuji, M.; Nakamura, T.;
Inamoto, N.; Yamamoto, Y. Tetrahedron Lett. 1987, 28,
6325. (c) Yamamoto, Y.; Maeda, K.; Tomimoto, K.; Mase,
T. Synlett 2002, 561.
(17) (a) Comins, D. L.; Huang, S.; McArdale, C. L.; Ingalls, C. L.
Org. Lett. 2001, 3, 469. (b) Comins, D. L.; Nolan, J. M. Org.
Lett. 2001, 3, 4255. (c) Mhaske, S. B.; Argade, N. P. J. Org.
Chem. 2004, 69, 4563. (d) Naka, H.; Akagi, Y.; Yamada,
K.; Imahori, T.; Kasahara, T.; Kondo, Y. Eur. J. Org. Chem.
2007, 4635. (e) Comins, D. L.; Odachi, P. W. Tetrahedron
Lett. 2008, 49, 569.
(18) Kondo, Y.; Asai, M.; Miura, T.; Uchiyama, M.; Sakamoto,
T. Org. Lett. 2001, 3, 13.
Organolithium Compounds, Vol. 2; Rappoport, Z.; Marek,
I., Eds.; Wiley: Chichester, 2006, Chap. 4, 295–379; see also
refs. 1, 2e, and 3.
(19) Mesityllithium-Mediated Carbolithiation Reactions of
N-(o-Iodobenzyl)pyrroles 3b,c: Synthesis of Pyrrolo[1,2-
b]isoquinolines – Typical Procedure for the Synthesis of
Benzyl 2-(7,8-Dimethoxy-5,10-dihydropyrrolo[1,2-
b]isoquinolin-10-yl)acetate (4b)
(7) For some representative examples, see: (a) Chamberlin,
A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H. J. Am.
Chem. Soc. 1988, 110, 4788. (b) Funk, R. L.; Bolton, G. L.;
Brummond, K. M.; Ellestad, K. E.; Stallman, J. B. J. Am.
Chem. Soc. 1993, 115, 7023. (c) Bailey, W. F.; Jiang, X.-L.;
McLeod, C. E. J. Org. Chem. 1995, 60, 7791. (d) Krief, A.;
Kenda, B.; Remacle, B. Tetrahedron 1996, 52, 7435.
(e) Coldham, I.; Hufton, R.; Price, K. N.; Rathmell, R. E.;
Snowdem, D. J.; Vennall, G. P. Synthesis 2001, 1523.
(f) Deng, K.; Bensari, A.; Cohen, T. J. Am. Chem. Soc. 2002,
124, 12106. (g) Sanz, R.; Ignacio, J. M.; Rodríguez, M. A.;
Fañanás, F. J.; Barluenga, J. Chem. Eur. J. 2007, 13, 4998.
(h) The procedure has also been extended to the
To a solution of mesityl bromide (0.1 mL, 0.65 mmol) in dry
THF (5 mL), t-BuLi (1.2 mL of a 1.1 M solution in hexane,
1.3 mmol) was added at –78 °C, and the reaction mixture
was stirred at –20 °C for 1 h. N-(o-Iodobenzyl) pyrroles 3b
(126 mg, 0.32 mmol) in dry THF (5 mL) was added at –105
°C, and the resulting mixture was stirred at this temperature
for 5 min. The reaction was quenched by the addition of sat.
NH4Cl (5 mL). Then, Et2O (10 mL) was added, the organic
layer was separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography (silica gel, 60% hexane–EtOAc)
afforded 4b as a colorless oil (113 mg, 92%). IR (CHCl3):
1734 cm–1. 1H NMR (300 MHz, CDCl3): d = 2.75 (d, J = 7.1
Hz, 2 H), 3.81 (s, 3 H), 3.88 (s, 3 H), 4.61 (t, J = 7.1 Hz, 1
H), 4.58 (s, 1 H), 4.61 (s, 1 H), 4.64 (s, 2 H), 6.01 (s, 1 H),
6.18 (t, J = 2.8 Hz, 1 H), 6.70 (s, 2 H), 6.82 (s, 1 H), 7.26–
corresponding alkyne derivatives. See, for instance: Wu, G.;
Cederbaum, F. E.; Negishi, E. Tetrahedron Lett. 1990, 31,
493.
(8) (a) Ross, G. A.; Koppang, M. D.; Bartak, D. E.; Woolsey,
N. F. J. Am. Chem. Soc. 1985, 107, 6742. (b) Harrowven,
D. C. Tetrahedron Lett. 1992, 33, 2879. (c) Bailey, W. F.;
Daskapan, T.; Rampalli, S. J. Org. Chem. 2003, 68, 1334.
Synlett 2008, No. 20, 3188–3192 © Thieme Stuttgart · New York

3192
S. Lage et al.
LETTER
7.35 (m, 5 H). 13C NMR (75.47 MHz, CDCl3): d = 35.3, 43.6,
47.1, 55.9, 66.2, 103.9, 108.2, 109.0, 110.7, 118.4, 124.1,
128.1, 128.4, 129.9, 135.6, 147.6, 148.1, 171.3. MS (EI):
m/z (%) = 378(6) [M+ + 1], 377(21) [M+], 287(17), 286(83),
242(7), 229(16), 228(100), 212(15), 184(10), 91(16).
HRMS: m/z calcd for C23H23NO4: 377.1627; found:
377.1638.
incorporation of deuterium into the acetyl group could be
observed by GC-MS.
(22) For representative examples, see: (a) Paleo, M. R.; Castedo,
L.; Domínguez, D. J. Org. Chem. 1993, 58, 2763.
(b) Gould, S. J.; Melville, C. R.; Cone, M. C.; Chen, J.;
Carney, J. R. J. Org. Chem. 1997, 62, 320. (c) Moreau, A.;
Lorion, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
J. Org. Chem. 2006, 71, 3303.
(23) (a) Aidhen, I. S.; Narasimham, N. S. Tetrahedron Lett. 1991,
32, 2171. (b) Kihara, M.; Kashimoto, M.; Kobayashi, Y.
Tetrahedron 1992, 48, 67.
(20) N-Benzylpyrroles 2b–f were prepared by alkylation of the
corresponding 2-acylpyrrole 5b–f with bromide 1 under
standard conditions (KOH, DMSO) as described in
Scheme 1 for 2a.
(21) In fact, when the reaction described in Table 3, entry 6
(t-BuLi, 2 equiv, –90 °C, 5 min) was quenched with MeOD,
Synlett 2008, No. 20, 3188–3192 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.