Intramolecular carbolithiation reactions in the construction of medium-sized rings. Synthesis of pyrroloisoquinolines, benzazepines, and benzazocines

Article abstract of DOI:10.1002/ejoc.201200994

Mesityllithium (MesLi) was found to be superior to butyllithium for the formation of aryllithium intermediates by iodine-lithium exchange. Subsequent intramolecular carbolithiation of the 2-alkenyl-substituted ortho-lithiated N-benzylpyrroles proceeded efficiently when the alkene was substituted with an electron-withdrawing group. The procedure is applicable to the construction of six-, seven-, and eight-membered rings, thus, opening new routes to pyrroloisoquinolines, benzazepines, and benzazocines. Although the use of (-)-sparteine as a chiral ligand led to low levels of enantioselection, enantiomerically pure isoquinolines could be synthesized by applying this protocol to the related pyrrolidines derived from proline, as the reactions proceeded with complete diastereoselectivity. Pyrroloisoquinolines, benzazepines, and benzazocines were be obtained by an intramolecular carbolithiation reaction of aryllithium intermediates bearing an electron-deficient alkene moiety. Enantiomerically pure pyrroloisoquinolines can be synthesized by applying this protocol to pyrrolidines derived from proline. Copyright

Full text of DOI:10.1002/ejoc.201200994

FULL PAPER
DOI: 10.1002/ejoc.201200994
Intramolecular Carbolithiation Reactions in the Construction of Medium-Sized
Rings. Synthesis of Pyrroloisoquinolines, Benzazepines, and Benzazocines
Oihane García-Calvo,[a] Estíbaliz Coya,[a] Sergio Lage,[a] Iain Coldham,*[b]
Nuria Sotomayor,[a] and Esther Lete*[a]
Keywords: Nitrogen heterocycles / Medium-ring compounds / Lithiation / Carbanions / Diastereoselectivity
Mesityllithium (MesLi) was found to be superior to butyllith-
ium for the formation of aryllithium intermediates by iodine–
lithium exchange. Subsequent intramolecular carbolithiation
of the 2-alkenyl-substituted ortho-lithiated N-benzylpyrroles
proceeded efficiently when the alkene was substituted with
an electron-withdrawing group. The procedure is applicable
to the construction of six-, seven-, and eight-membered
rings, thus, opening new routes to pyrroloisoquinolines,
benzazepines, and benzazocines. Although the use of (–)-
sparteine as a chiral ligand led to low levels of enantioselec-
tion, enantiomerically pure isoquinolines could be synthe-
sized by applying this protocol to the related pyrrolidines de-
rived from proline, as the reactions proceeded with complete
diastereoselectivity.
Introduction
Pyrrolo[1,2-b]isoquinolines are heterocyclic moieties
found in several natural products, such as the lycorine class
of Amaryllidaceae alkaloids,[1] the phenanthroindolizidine
alkaloids,[2] and in many molecules exhibiting useful thera-
peutic properties. For example, bis(hydroxymethyl)- and
bis(alkylcarbamate)-5,10-dihydropyrrolo[1,2-b]isoquin-
olines possess antitumor activity,[3] and 10-aminobenzo-
indolizidines have been evaluated as acetyl cholinesterase
inhibitors for antiamnesic action[4] in the treatment of Alz-
heimer’s disease, senile dementia, and other conditions
characterized by memory loss. On the other hand, the pyr-
rolobenzazepine core is present in Cephalotaxus alkaloids,[5]
which have been used in the treatment of myeloid leuke-
mia.[6] In addition to their muscle relaxant, antihyperten-
sive, and antipsychotic properties,[7] the use of some 9-sub-
stituted pyrrolo[2,1-b][3]benzazepines as advanced interme-
diates in the syntheses of these alkaloids has attracted sig-
nificant attention.[8] The 2-benzazocine ring system is also
an important structural pattern present in natural (e.g., bu-
flavine[9]) and synthetic products that display biological ac-
tivity. For instance, indolobenzazocines can be used as anti-
viral agents[10] (see Figure 1).
Figure 1. Pyrroloisoquinoline, benzazepine, and benzazocine
frameworks in natural products.
The development of new strategies for the synthesis of
medium-sized heterocycles still remains a challenge in or-
ganic synthesis.[11] Previously reported methods for prepar-
ing benzazepines and benzazocines mainly involve RCM
(ring-closing metathesis), Pd0-catalyzed cyclization,[12] and
intramolecular α-amidoalkylation reactions.[13]
In this context, we have shown that N-(o-iodophenethyl)-
and N-(o-iodophenylpropyl)pyrrole-2-carboxamides toler-
ate iodine–lithium exchange reaction conditions to allow
the efficient syntheses of pyrrolo[1,2-a]benzazepines and
pyrrolo[1,2-a]benzazocines through a cyclization onto a
carbonyl group (Parham cyclization).[14] The development
of an intramolecular carbolithiation strategy for the con-
struction of six-, seven-, and eight-membered rings through
a cyclization onto an alkene is the subject of this account.
[a] Departamento de Química Orgánica II, Facultad de Ciencia y
Tecnología, Universidad del País Vasco/Euskal Herriko
Unibertsitatea UPV/EHU,
Apdo. 644, 48080 Bilbao, Spain
Fax: +34-946012748
E-mail: esther.lete@ehu.es
Homepage: http://www.ehu.es/oms
[b] Department of Chemistry, University of Sheffield,
Brook Hill, Sheffield S3 7HF, UK
E-mail: i.coldham@sheffield.ac.uk
Homepage: http://www.sheffield.ac.uk/chemistry
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200994.
1460
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1460–1470

Intramolecular Carbolithiation
The carbolithiation reaction has attracted considerable plying these reactions to the syntheses of larger rings (azep-
interest among synthetic organic chemists, as it offers an ines and azocines) and the possibility of carrying out enan-
attractive pathway for the efficient construction of new C– tioselective and diastereoselective transformations in the
C bonds with the possibility of introducing further func- syntheses of enantiopure derivatives. We disclose here the
tionalization by trapping the reactive organolithium inter- full details of our investigations.
mediates with electrophiles. When alkenes are used, up to
two contiguous stereogenic centers may be generated, which
Results and Discussion
may be controlled by using chiral ligands for lithium, and
so opening new opportunities for application of this meth-
odology to asymmetric synthesis. The intramolecular vari-
ant of this reaction has been applied mainly with alkyl- and
alkenyllithium intermediates, though there are also exam-
ples of a cycloisomerization reaction for alkenyl-substituted
aryllithium intermediates, generated by a metal–halogen ex-
change.[15] In particular, intramolecular carbolithiation is
well suited for the diastereoselective construction of five-
membered rings through a 5-exo-trig cyclization process, as
has been shown in the synthesis of both carbocycles[16] and
heterocycles.[17] However, there are few precedents for the
formation of six-membered cycles by the carbocyclization
of unactivated double bonds, and its application to me-
dium-sized rings has not yet been reported. To achieve a 6-
exo cyclization, it is necessary to use a substituted alkene
to stabilize the resulting organolithium compound. Thus,
aryllithium reagents prepared by the bromine–lithium ex-
change of chiral 2-(o-bromophenyl)-substituted perhydro-
1,3-benzoxazines can participate in an intramolecular 6-exo
carbolithiation to give diastereomeric isoquinoline deriva-
tives in almost quantitative yield and in enantiomerically
pure form, when the alkene carries a phenyl or a leaving
group α to the double bond (SN2Ј pathway).[18]
To test the carbolithiation reactions, a series of N-(o-
iodobenzyl)pyrroles 2a–2d were prepared from commer-
cially available pyrrole-2-carbaldehyde through an alkyl-
ation reaction [KOH, DMSO (dimethyl sulfoxide), room
temp., 4 h] with 2-iodo-4,5-dimethoxybenzyl bromide[14b]
and subsequent Wittig olefination of the N-benzylpyrrole-
2-carbaldehyde (1) with the corresponding phosphorus
ylides (see Scheme 1). N-(o-Iodobenzyl)pyrroles 2c and 2d
were obtained in high yields as a single E diastereomer, but
2b was obtained as a diastereomer mixture (E/Z, 1.1:1),
which could not be separated by usual chromatographic
methods (see Table 1).[23]
Scheme 1.
Table 1. Synthesis of N-(o-iodobenzyl)pyrroles 2a–2e.
Entry Solvent Temp. Time R1
[h]
2
%
Z/E
Yield[a]
In this context, enantioenriched pyrrolizidines have been
prepared by intramolecular carbolithiation of chiral α-ami-
noorganolithiums, generated by a tin–lithium exchange
from the corresponding enantiomerically enriched stann-
anes.[19] This cyclization can be extended to the formation
of six-membered rings, obtaining indolizidines in good yield
and high diastereoselectivity. However, the slow rate of cy-
1
2
3
4
THF
THF
CH2Cl2 reflux
CH2Cl2 reflux
r.t.
r.t.
6
H
Ph
2a
2b
2c
80
98
85
97
–
12
96
96
1:1.1
Ͻ1:99
Ͻ1:99
CO2Bn
CONEt2 2d
[a] Yield of isolated product.
We first studied the carbolithiation reactions of N-(o-
clization results in partial racemization. The use of a phen- iodobenzyl)pyrrole (2a) with tBuLi/TMEDA [(N,N,NЈ,NЈ-
ylthio-substituted alkene favors the cyclization, resulting in tetramethyl-1,2-ethylenediamine), see Scheme 2 and
an improved optical purity of the indolizidines.[20] On the Table 2], starting from the previously used conditions.[24,25]
other hand, 2,4-disubstituted tetrahydroquinolines have However, although the iodine–lithium exchange occurred
been obtained through an intramolecular carbolithiation of efficiently, intramolecular carbolithiation did not take
aryllithiums obtained from N-alkenyl-substituted o-iodoan- place, and dehalogenated product 4a was obtained (see
ilines, when the alkene is substituted with an amide group. Table 2, Entry 1). Using a less coordinating solvent (i.e., tol-
When the reaction is carried out in the presence of (–)-spar- uene) at –90 °C and allowing the mixture to warm to 0 °C
teine, moderate diastereoselectivities (up to 77:23) and high also resulted in dehalogenation (see Table 2, Entry 2), and a
enantioselectivities (ee up to 94%) were obtained when low conversion (60%) was obtained with 1 equiv. of tBuLi/
using the Weinreb amide derivatives.[21]
TMEDA (see Table 2, Entry 3). In all cases, the addition of
We were interested in the application of this cyclization tBuLi to the unsubstituted alkene in 2a was competitive
to the syntheses of pyrrolo[1,2-b]isoquinoline systems. with the cyclization reaction (see Supporting Information).
Thus, in a preliminary communication, we reported that 6- The introduction of a phenyl group to the alkene to stabi-
exo-trig intramolecular carbolithiation of N-(o-iodobenzyl)- lize the organolithium compound generated by the carboli-
pyrroles could take place. However, in this case, besides the thiation[26] also did not favor the intramolecular reaction,
activation of the alkene, the use of mesityllithium (MesLi) and deiodinated N-benzylpyrrole 4b was the only product
as a metalating agent was required to avoid 1,2- or 1,4- (see Table 2, Entries 4 and 5). It has been shown that the
addition of the alkyllithium compound to the unsaturated rate of carbolithiation can be increased by performing the
system.[22] With these precedents, we were interested in ap- reactions at higher temperatures,[27] so the reaction mixtures
Eur. J. Org. Chem. 2013, 1460–1470
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1461

I. Coldham, E. Lete et al.
FULL PAPER
were warmed to 50 °C with toluene as the solvent to avoid ium (MesLi) is described as a strongly basic, nonnucleo-
a protonation of the aryllithium intermediate (see Table 2, philic, and selective reagent,[28] which has been used mainly
Entry 6). However, similar results were obtained. Therefore, for deprotonation reactions in organic synthesis.[29] Only a
we studied the carbolithiation reactions with 2c, where the few examples of its use in aromatic metalation[30] or halo-
alkene is substituted with an electron-withdrawing group gen–lithium exchange reactions[31] are reported. Thus, as
(R1 = CO2Bn). Unfortunately, under standard conditions, shown in Table 3, the iodine–lithium exchange reaction was
the direct additions of tBuLi to both the alkene and ester efficiently performed with MesLi, avoiding in all cases the
moieties were competitive reactions, yielding a mixture of direct addition of the organolithium reagent to the alkene.
products (see Supporting Information, Entry 7). Different However, although the iodine–lithium exchange took place
reaction conditions were tested, and although cyclization smoothly under these conditions, unsubstituted alkene 2a
took place in the absence of TMEDA (see Table 2, En- and phenyl-substituted alkene 2b were unreactive towards
tries 8–10), the addition of tBuLi to the ester moiety could cyclization (see Table 3, Entries 1 and 4), and the benzylpyr-
not be avoided. Even performing the reaction at –90 °C af- roles 4a and 4b were obtained. At higher temperatures (–20
forded the pyrroloisoquinoline 3c in low yield.
or 0 °C, see Table 3, Entries 2 and 3), decomposition of the
aryllithium intermediate was observed with 2a, whereas the
reaction of 2b led to 4b in high yield, even at room tempera-
ture (see Table 3, Entry 5). On the other hand, once the
aryllithium intermediate was formed, the presence of an es-
ter or amide group on the alkene enhanced the rate of cycli-
zation, as pyrroloisoquinolines 3c and 3d were obtained in
high yields at low temperature (–78 or –105 °C) and in only
5 min (see Table 3, Entries 6–9). It should be noted that it
was not necessary to use TMEDA or other additives to ac-
celerate the reactions or to improve the yields. In view of
these results, we decided to investigate the feasibility of
using this procedure to construct a seven- or eight-mem-
bered ring, opening new access to the pyrrolobenzazepine
and pyrrolobenzazocine skeletons. Thus, the required 1-(2-
iodo-4,5-dimethoxyphenylethyl)- and 1-(2-iodo-4,5-dimeth-
oxyphenylpropyl)pyrroles 7a and 7b, which incorporate an
amide group on the alkene, were obtained by alkylation of
pyrrole-2-carbaldehyde with tosylate 5a or mesylate 5b, fol-
lowed by a Wittig olefination as described in Scheme 3.[32]
In fact, the intramolecular 7-exo carbolithiation reaction of
7a occurred efficiently in just 5 min using 2 equiv. of mes-
ityllithium at –105 °C to afford the pyrrolo[1,2-b][3]benz-
azepine 8 in high yield. The cyclization to obtain the eight-
membered ring of pyrrolo[1,2-b][3]benzazocine 9 was less
efficient, as depicted in Table 4. Thus, under the same con-
ditions (MesLi, –105 °C, 5 min), 9 was obtained in a 67%
yield, as estimated by 1H NMR spectroscopy.[33] The use of
TMEDA did not affect the results significantly, and similar
yields were obtained at –78 °C. The isolation of 9 from the
crude reaction mixture, where the dehalogenated starting
Scheme 2.
Table 2. Carbolithiation reactions of 2a–2d with tert-butyllithium.
Entry Substrate tBuLi TMEDA Temp.
Product % Yield[a]
equiv.
equiv.
[°C]
1
2
3
4
2a
2a
2a
2b
2
2
1
2
2
2[c]
1
–78 to 0
–90 to 0
–78 to 0
–78 to
r.t.
4a[b]
4a
4a
26
32
17
72
2
4b
5
2b
2
–
–78 to
r.t.
50
–78 to 0
–78
–78
–90
–78
–78
–78
4b
69
6
7
8
9
10
11
12
13
14
2b
2c
2c
2c
2c
2d
2d
2d
2d
2
2
2
1
2
1
2
1
1
2[c]
2
–
–
–
–
2
1
1
4b
45
–
[b]
3c[b]
3c
3c
39
38
42
41
27
39
31
3d
3d[b]
3d
–105
3d
[a] Yield of isolated product. [b] See Supporting Information for
isolation of additional byproducts. [c] The reactions were carried
out in toluene.
When an amide was used as the electron-withdrawing material was detected as a byproduct, was not easily ac-
group on the alkene moiety (2d, R1 = CONEt2), the 1,2-
addition was avoided. However, the direct 1,4-addition of
tBuLi, in the absence of TMEDA, was still competitive, re-
sulting in a lower yield of pyrroloisoquinoline 3d (see Entry Substrate Temp. [°C]
Table 3. Carbolithiation reactions of 2a–d with mesityllithium.
Time
Product
% Yield[a]
Table 2, Entry 11). The yield of 3d could not be improved
in the presence of TMEDA (see Table 2, Entry 12) or by
lowering the temperature or the number of equivalents of
tBuLi (see Table 2, Entries 13 and 14). The reactions were
quite fast and completed in just 10 min, even in the absence
of TMEDA.
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2b
2c
2c
2d
2d
–78
–20
0
4 h
20 h
3 h
4a
42
16
–
95
86
80
92
83
90
4a
[b]
–78
3 h
4b
4b
3c
3c
3d
3d
–78 to r.t.
–78
–105
–78
22 h
5 min
5 min
5 min
5 min
To avoid the competitive 1,2 and 1,4-additions, a more
bulky and less nucleophilic reagent was chosen for the io-
–105
dine–lithium exchange reaction. In this context, mesityllith- [a] Yield of isolated product. [b] Complex mixture of products.
1462 Eur. J. Org. Chem. 2013, 1460–1470
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Intramolecular Carbolithiation
complished by chromatographic methods, thereby lowering 37 %) was obtained. Several attempts were made to improve
the yield of pure 9 to 42%. Longer reaction times or higher the enantioselectivity, but using nBuLi at lower temperature
temperatures did not improve the results.
or inversing the addition conditions did not significantly
improve the ee value or yield.[36]
Scheme 4.
In view of these results and considering that the natural
pyrroloisoquinoline framework incorporates a pyrrolidine
ring (see Figure 1), we decided to study a diastereoselective
variant of the intramolecular carbolithiation reaction on
the pyrrolidine derivatives to access enantiomerically pure
pyrroloisoquinolines. Recently, we have shown that the in-
tramolecular carbolithiation of a 2-alkenyl-substituted pyr-
rolidine takes place with complete diastereoselectivity.[37]
With these precedents, we decided to use this approach for
the syntheses of biologically important indolizidine targets
in enantiomerically pure form. Thus, the enantiomerically
pure N-(o-iodobenzyl)pyrrolidines 12a and 12b were pre-
pared from commercially available protected l-prolinal by
using the standard procedures outlined in Scheme 5. The
Wittig olefination of 10 followed by deprotection with TFA
(trifluoroacetic acid) and subsequent N-alkylation with 2-
iodo-4,5-dimethoxybenzyl bromide afforded the corre-
sponding α-alkenyl-substituted pyrrolidines (S)-12a and
(S)-12b in very good yields and without epimerization at
the stereogenic center (99%ee), determined by chiral sta-
tionary phase HPLC.[38] In this case, we prepared the Wein-
Scheme 3.
Table 4. Carbolithiation reactions of 7b with mesityllithium.
Entry
equiv. TMEDA
Temp. [°C]
% Yield[a]
1
2
3
4
–
2
–
2
–105
–105
–78
67
68
66
–78
63[b]
1
[a] Calculated by H NMR spectroscopy. [b] 42% yield of isolated
product.
Our next step was to study the possibility of performing
the carbolithiation reactions in an enantioselective fashion
in the presence of a chiral ligand for lithium. In this con-
text, the chiral bidentate amine (–)-sparteine[34] has been
used in the formation of five-membered rings with high
levels of stereocontol.[35] Several reaction conditions were
tested using compound 2d. The best results, shown in
Scheme 4, were obtained when 2d was treated with nBuLi
and (–)-sparteine, using toluene as the solvent to allow the
coordination of the organolithium intermediate with the
amine. However, although the carbolithiation reaction af-
forded the pyrroloisoquinoline 3d in moderate yields and
avoided side reactions, a low enantiomeric excess (ee up to Scheme 5.
Eur. J. Org. Chem. 2013, 1460–1470
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1463

I. Coldham, E. Lete et al.
FULL PAPER
The NMR spectroscopic data were recorded at 20–25 °C and at
reb amide derivative 12b, as this group has proven to be
more effective than the diethyl amide in related intramolec-
ular carbolithiations.[21]
To optimize the intramolecular carbolithiation reaction
conditions, different metalating agents, the presence or ab-
sence of additives, and different solvents and temperatures
were evaluated (see Table 5). Under analogous conditions
previously used for the pyrroles (MesLi, THF, –105 °C), cy-
clization took place with complete stereoselectivity to af-
1
300 or 500 MHz for H NMR and at 75.5 or 125.7 MHz for 13C
NMR in CDCl3 solutions, unless otherwise stated. Assignments of
1
individual 13C and H NMR resonances are supported by DEPT
and 2D correlation experiments [COSY, HSQCed (heteronuclear
single quantum correlation), or HMBC]. Mass spectra were re-
corded using electron impact (EI) at 70 eV or chemical ionization
(CI) at 230 eV. The exact mass was obtained using a TOF (time-
of-flight) detector. TLC was carried out with 0.2 mm thick silica
gel plates. The visualizations were accomplished by using UV light.
ford the pyrrolo[1,2-b]isoquinolines 13a and 13b as single Flash column chromatography was performed with silica gel (230–
400 mesh) or alumina (70–230 mesh). Chiral stationary phase
HPLC was performed using Chiralcel ASH or OD columns
(0.46 cmϫ25 cm). All of the solvents used in the reactions were
anhydrous and purified according to standard procedures.[41] Peri-
odically, prior to use, both n- and tert-butyllithium were titrated
with diphenylacetic acid or N-benzylbenzamide. All air- or moist-
ure-sensitive reactions were performed under argon, and the glass-
ware was dried (130 °C) and purged with argon.
trans-(10R,10aS)-diastereomers in enantiomerically pure
form (ee Ͼ99 %). In contrast to the results obtained from
the corresponding pyrrole derivatives (see above), 1,2- or
1,4-intermolecular addition products were not detected,
when the reactions were carried out with nBuLi in the pres-
ence of TMEDA at –78 °C, obtaining products 13a and 13b
in comparable yields. A reversal in the diastereoselection
has been reported when (–)-sparteine was used instead of
TMEDA in related processes,[39] which prompted us to per-
form the carbolithiation reaction in the presence of this chi-
ral bidentate ligand. As shown (see Table 5, Entries 3 and
6), the stereochemical outcomes were the same as those ob-
tained with TMEDA, affording the same trans-(10R,10aS)-
diastereomers in enantiomerically pure form (ee Ͼ99 %) as
the only diastereomer.[40] As shown in Table 5, the use of
1-(2-Iodo-4,5-dimethoxybenzyl)-1H-pyrrole-2-carbaldehyde (1):[23]
1H-Pyrrole-2-carbaldehyde (1.00 g, 10.5 mmol) was added over a
suspension of powdered KOH (2.40 g, 42.1 mmol) in DMSO
(20 mL). The mixture was stirred at room temperature for 2 h, and
2-iodo-4,5-dimethoxybenzyl bromide (7.50 g, 21.0 mmol) was
added. The reaction mixture was then stirred for 4 h. H2O (40 mL)
was added, and the resulting aqueous phase was extracted with
CH2Cl2 (3ϫ50 mL). The combined organic extracts were washed
Weinreb amide 12b offered comparable results to diethyl with brine (3ϫ40 mL), dried with Na2SO4, and concentrated in
vacuo. Flash column chromatography (silica gel, 30% hexane/Ac-
OEt) of the resulting residue afforded 1, which was crystallized
from a hexane/AcOEt mixture (3.50 g, 89%). The characterization
data were identical to those reported in literature.[23]
amide 12a.
Table 5. Carbolithiation reactions of 12a,b with tert-butyllithium.
Entry Substrate
RLi
Additive
Solvent Temp. % Yield[a]
[°C]
1-(2-Iodo-4,5-dimethoxybenzyl)-2-vinyl-1H-pyrrole (2a): nBuLi
(1.2 m solution in hexane, 0.78 mL, 1.4 mmol) was added over a
suspension of methyltriphenylphosphonium bromide (330 mg,
1.0 mmol) in dry THF (10 mL) at 0 °C, and the reaction mixture
was stirred at this temperature for 30 min. Then, a solution
of 1-(2-iodo-4,5-dimethoxybenzyl)-1H-pyrrole-2-carbaldehyde (1)
(250 mg, 0.67 mmol) in THF (5 mL) was added at –78 °C, and the
resulting reaction mixture was stirred at this temperature for 20 min
and then at room temperature for 6 h. A saturated aqueous solu-
tion of NH4Cl (10 mL) was added, and the aqueous phase was
extracted with Et2O (2ϫ30 mL) and then CH2Cl2 (2ϫ30 mL). The
combined organic extracts were dried with Na2SO4 and concen-
trated in vacuo. Flash column chromatography (silica gel, 10% hex-
ane/AcOEt) of the resulting residue afforded 2a (198 mg, 80%) as
1
2
3
4
5
6
(S)-12a
(S)-12a
(S)-12a
(S)-12b
(S)-12b
(S)-12b
MesLi
nBuLi
–
THF
THF
–105
–78
66
60
73
65
58
68
TMEDA
nBuLi (–)-sparteine toluene –90
MesLi
nBuLi
–
THF
THF
–105
–78
TMEDA
nBuLi (–)-sparteine toluene –90
[a] Yield of isolated product. The ee was determined by chiral sta-
tionary phase HPLC and comparison with a racemic sample.
Conclusions
Intramolecular carbolithiation reactions of 2-alkenyl-
substituted N-benzylpyrroles constitutes an efficient route
to pyrrolo[1,2-b]isoquinolines, when the internal alkene be-
ars an electron-withdrawing group and a nonnucleophilic
metalating agent, such as MesLi, is used. The procedure
is applicable to the construction of six-, seven-, and eight-
membered rings, thus, opening new routes to benzazepines
and benzazocines. Similarly, the 6-exo carbolithiation of 2-
alkenylpyrrolidines takes place with complete diastereo-
selectivity, allowing the synthesis of enantiomerically pure
hexahydropyrrolo[1,2-b]isoquinolines in high yields.
a colorless oil; m.p. 105–106 °C (Et O). IR (film): ν = 1645 cm–1.
˜
2
1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.61 (s, 3 H, OCH3), 3.85
(s, 3 H, OCH3), 4.95–5.01 (m, 1 H, HC=CHaHb), 5.00 (s, 2 H,
CH2), 5.46 (dd, J = 17.0, 1.2 Hz, 1 H, HC=CHaHb), 5.97 (s, 1 H,
Ar H6), 6.20 (t, J = 3.0 Hz, 1 H, pyrrole H4), 6.38–6.42 (m, 1 H,
HC=CHaHb), 6.47 (t, J = 3.0 Hz, 1 H, pyrrole H3), 6.66 (t, J =
3.0 Hz, 1 H, pyrrole H5), 7.24 (s, 1 H, Ar H3) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C): δ = 55.1, 55.5, 56.1, 84.1, 106.9, 108.7,
110.3, 111.5, 121.1, 122.7, 125.1, 131.8, 132.6, 148.7, 149.8 ppm.
MS (EI): m/z (%) = 370 (3) [M + 1]+, 369 (15) [M]+, 278 (11), 277
(100), 243 (15), 242 (64), 150 (11). HRMS (CI): calcd. for
C15H17INO2 [MH]+ 370.0304; found 370.0292.
(E)- and (Z)-1-(2-Iodo-4,5-dimethoxybenzyl)-2-styryl-1H-pyrrole
(2b):[23] nBuLi (1.2 m solution in hexane, 0.76 mL, 0.91 mmol) was
added over a suspension of benzyltriphenylphosphonium chloride
(390 mg, 1.00 mmol) in dry THF (10 mL) at 0 °C, and the resulting
Experimental Section
General Methods: Melting points were determined using unsealed
capillary tubes. IR spectra were obtained as films over NaCl pellets.
1464
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1460–1470

Intramolecular Carbolithiation
reaction mixture was stirred for 15 min. Then, a solution of N-
benzylpyrrolecarbaldehyde (1) (250 mg, 0.67 mmol) in dry THF
(5 mL) was added, and the resulting reaction mixture was stirred
at room temperature for 12 h. The reaction was quenched by the
addition of a saturated NH4Cl solution (15 mL). Et2O (10 mL) and
(E)- and (Z)-1-(3,4-Dimethoxybenzyl)-2-styryl-1H-pyrrole (4b): Ac-
cording to the general procedure, 2b (142 mg, 0.32 mmol) was
treated with MesLi (0.65 mmol), which was prepared from mesityl
bromide (0.1 mL, 0.65 mmol) and tBuLi (1.0 m solution in hexane,
1.3 mL, 1.3 mmol), at –78 °C. The reaction mixture was stirred for
H2O (10 mL) were added. The aqueous phase was extracted with 3 h. After workup, flash column chromatography (silica gel, 80%
CH2Cl2 (3ϫ10 mL). The combined organic extracts were dried
with Na2SO4 and concentrated in vacuo. Flash column chromatog-
raphy (silica gel, 80% hexane/AcOEt) of the resulting residue af-
forded 2b (290 mg, 98%) as a colorless oil and as a mixture of
isomers (Z/E, 1:1.1). The characterization data were identical to
those reported in literature.[23]
hexane/AcOEt) afforded 4b (100 mg, 95%) as a colorless oil and as
a mixture of isomers (Z/E, 1:1.1): IR (film): ν = 2920, 1700 cm–1.
˜
1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.80 (s, 3 H, OCH3, Z
isomer), 3.82 (s, 3 H, OCH3, Z isomer) 3.86 (s, 6 H, OCH3, E
isomer), 5.00 (s, 2 H, CH2, Z isomer), 5.10 (s, 2 H, CH2, E isomer),
6.10 (t, J = 3.0 Hz, 1 H, pyrrole H4, Z isomer), 6.15 (d, J = 3.0 Hz,
1 H, pyrrole H3, Z isomer), 6.24 (t, J = 3.0 Hz, 1 H, pyrrole H4, E
isomer), 6.34 (d, J = 12.2 Hz, 1 H, HC=CHPh, Z isomer), 6.42 (d,
J = 12.2 Hz, 1 H, HC=CHPh, Z isomer), 6.57 (t, J = 3.0 Hz, 1 H,
pyrrole H3, E isomer), 6.60–6.67 (m, 5 H, 4 Ar H, both isomers,
pyrrole H5, Z isomer), 6.73 (d, J = 1.6 Hz, 1 H, pyrrole H5, E
isomer), 6.80–6.84 (m, 2 H, Ar H, both isomers), 6.88 (d, J =
16.1 Hz, 1 H, HC=CHPh, E isomer), 6.94 (d, J = 16.1 Hz, 1 H,
HC=CHPh, E isomer), 7.19–7.39 (m, 10 H, Ph, both isomers) ppm.
13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 50.3 (both isomers), 55.9
(both isomers), 107.1 (E isomer), 108.2 (Z isomer), 108.8 (E iso-
mer), 109.8 (Z isomer), 109.9 (both isomers), 111.2 (both isomers),
117.2 (E isomer), 118.8 (Z isomer), 119.0 (both isomers), 122.0 (Z
isomer), 123.2 (E isomer), 126.0 (Z isomer), 126.3 (E isomer), 127.1
(Z isomer), 128.3 (E isomer), 128.5 (Z isomer), 128.6 (E isomer),
128.8 (E isomer), 129.3 (Z isomer), 130.6 (both isomers), 131.8
(both isomers), 137.8 (both isomers), 148.4 (both isomers), 149.2
(both isomers) ppm. MS (EI): m/z (%) = 319 (27) [M]+, 218 (23),
151 (100), 131 (15), 97 (10). HRMS (EI): calcd for C21H21NO2
319.1572; found 319.1592.
(E)-Benzyl 3-[1-(2-Iodo-4,5-dimethoxybenzyl)-1H-pyrrol-2-yl]acryl-
ate (2c):[23] Benzyl 2-(triphenylphosphoranylidene)acetate (11.1 g,
27.0 mmol) was added in portions to a refluxing solution of N-
benzylpyrrole 1 (1.0 g, 2.7 mmol) in CH2Cl2 (40 mL) over a 4 d
period. The crude reaction mixture was washed with H2O
(2ϫ30 mL), dried with Na2SO4, and concentrated in vacuo. Flash
column chromatography (silica gel, 30% hexane/AcOEt) of the re-
sulting residue afforded 2c (1.1 g, 85%) as a colorless oil. The char-
acterization data were identical to those reported in literature.[23]
(E)-N,N-Diethyl-3-[1-(2-iodo-4,5-dimethoxybenzyl)-1H-pyrrol-2-yl]-
acrylamide (2d):[23] N,N-Diethyl-2-(triphenylphosphoranylidene)-
acetamide (4.0 g, 10.8 mmol) was added in portions to a refluxing
solution of N-benzylpyrrole (1) (400 mg, 1.1 mmol) in CH2Cl2
(40 mL) over a 4 d period. The crude reaction mixture was washed
with H2O (2ϫ30 mL), dried with Na2SO4, and concentrated in
vacuo. Flash column chromatography (silica gel, 60% hexane/Ac-
OEt) of the resulting residue afforded 2d as a white solid, which
was crystallized from hexane/AcOEt (0.49 g, 97%). The characteri-
zation data were identical to those reported in literature.[23]
Benzyl 2-(7,8-Dimethoxy-5,10-dihydropyrrolo[1,2-b]isoquinolin-10-
yl)acetate (3c): According to the general procedure, 2c (126 mg,
0.32 mmol) was treated with MesLi (0.65 mmol), which was pre-
pared from mesityl bromide (0.1 mL, 0.65 mmol) and tBuLi (1.1 m
solution in hexane, 1.2 mL, 1.3 mmol), at –105 °C. The reaction
mixture was stirred for 5 min. After workup, flash column
chromatography (silica gel, 60% hexane/AcOEt) afforded 3c
General Procedure for MesLi-Mediated Cyclization Reactions of N-
(o-Iodobenzyl)pyrroles 2a–2d: To a solution of mesityl bromide
(2 mmol) in dry THF (15 mL) was added tBuLi (4 mmol) at
–78 °C, and the resulting mixture was stirred at –20 °C for 1 h. The
reaction mixture was cooled again to –78 °C, and a solution of
one of the N-(o-iodobenzyl)pyrroles 2a–2d (1 mmol) in dry THF
(15 mL) was added at the temperature indicated in Table 3. The
reaction was quenched by the addition of a saturated NH4Cl solu-
tion (10 mL), and then Et2O (15 mL) was added. The organic layer
was separated, and the aqueous phase was extracted with CH2Cl2
(3ϫ15 mL). The combined organic extracts were dried with
Na2SO4 and concentrated in vacuo.
(113 mg, 92%) as a colorless oil. IR (film): ν = 1735 cm–1. 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 2.75 (d, J = 7.1 Hz, 2 H,
CH2CO2Bn), 3.81 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 4.61 (t, J
= 7.1 Hz, 1 H, H10), 4.97–5.02 (m, 2 H, 2 H5), 5.10 (s, 2 H,
OCH2Ph), 6.01 (br. s, 1 H, H1), 6.18 (t, J = 3.0 Hz, 1 H, H2), 6.70
(br. s, 2 H, H3, H9), 6.82 (s, 1 H, H6), 7.26–7.35 (m, 5 H, Ph) ppm.
13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 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 ppm. MS (EI): m/z (%) = 377 (21) [M]+,
287 (17), 286 (83), 242 (7), 229 (16), 228 (100), 212 (15), 184 (10), 91
(16). HRMS (EI): calcd. for C23H23NO4 377.1627; found 377.1630.
N-(3,4-Dimethoxybenzyl)-2-vinylpyrrole (4a): According to the ge-
neral procedure, 2a (126 mg, 0.32 mmol) was treated with MesLi
(0.65 mmol), which was prepared from mesityl bromide (0.1 mL,
0.65 mmol) and tBuLi (1.1 m solution in hexane, 1.3 mL,
1.40 mmol), at –78 °C. The reaction mixture was stirred for 4 h.
After workup, flash column chromatography (silica gel, 90% hex-
ane/AcOEt) afforded 4a (33 mg, 42%) as a colorless oil. IR (film):
2-(7,8-Dimethoxy-5,10-dihydropyrrolo[1,2-b]isoquinolin-10-yl)-N,N-di-
ethylacetamide (3d): According to the general procedure, 2d
(150 mg, 0.32 mmol) was treated with MesLi (0.65 mmol), which
ν = 2935, 1640 cm–1. 1H NMR (300 MHz, CDCl , 25 °C): δ = 3.81 was prepared from mesityl bromide (0.1 mL, 0.65 mmol) and tBuLi
˜
3
(s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.99 (dd, J = 12.0, 1.5 Hz, 1
(1.0 m solution in hexane, 1.3 mL, 1.3 mmol), at –105 °C. The reac-
H, HC=CHaHb), 5.06 (s, 2 H, CH2), 5.48 (dd, J = 17.5, 1.5 Hz, 1 tion mixture was stirred for 5 min. After workup, flash column
H, HC=CHaHb), 6.17 (t, J = 3.5 Hz, 1 H, pyrrole H4), 6.45 (t, J =
3.5 Hz, 1 H, pyrrole H3), 6.49 (dd, J = 17.5, 12.0 Hz, 1 H,
chromatography (silica gel, 60% hexane/AcOEt) afforded 3d
(92 mg, 90%) as a colorless oil. IR (film): ν = 1625 cm–1. 1H NMR
˜
HC=CHaHb), 6.54–6.67 (m, 3 H, Ar H2, Ar H6, pyrrole H5), 6.80 (300 MHz, CDCl3, 25 °C): δ = 0.84 (t, J = 7.5 Hz, 3 H, CH3), 1.10
(d, J = 8.5 Hz, 1 H, Ar H5) ppm. 13C NMR (75.5 MHz, CDCl3,
25 °C): δ = 50.2, 55.7, 55.8, 106.6, 108.2, 109.5, 111.1, 111.3, 118.6, 2.90 (q, J = 7.5 Hz, 2 H, CH2), 3.21–3.47 (m, 2 H, CH2), 3.85 (s,
122.6, 125.3, 130.5, 131.8, 148.2, 149.1 ppm. MS (EI): m/z (%) =
3 H, OCH3), 3.86 (s, 3 H, OCH3), 4.75 (t, J = 7.2 Hz, 1 H, H10),
243 (14) [M]+, 152 (11), 151 (100), 107 (9), 106 (6), 77 (5). HRMS 4.98 (d, J = 15.5 Hz, 1 H, H5a), 5.08 (d, J = 15.5 Hz, 1 H, H5b),
(CI): calcd. for C15H18NO2 [MH]+ 244.1338; found 244.1347. 6.02 (dd, J = 3.0, 1.6 Hz, 1 H, H1), 6.15 (t, J = 3.0 Hz, 1 H, H2),
(t, J = 7.5 Hz, 3 H, CH3), 2.60 (d, J = 7.2 Hz, 2 H, CH2CONEt2),
Eur. J. Org. Chem. 2013, 1460–1470
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1465

I. Coldham, E. Lete et al.
FULL PAPER
6.69 (br. s, 2 H, H3, H9), 6.94 (s, 1 H, H6) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C): δ = 13.1, 14.1, 35.9, 40.6, 42.1, 47.1,
55.9, 104.1, 108.3, 108.8, 111.3, 118.1, 123.6, 129.4, 130.6, 147.5,
170.1 ppm. MS (EI): m/z (%) = 343 (12) [M + 1]+, 342 (40) [M]+,
243 (12), 242 (67), 241 (49), 240 (10), 229 (13), 228 (100), 227 (95),
226 (11), 212 (20), 197 (11), 184 (21), 183 (14), 167 (14), 155 (10),
Na2SO4, and concentrated in vacuo. Flash column chromatography
(silica gel, 40% hexane/AcOEt) of the resulting residue afforded 7a
as a white solid, which was crystallized from hexane/AcOEt (3.5 g,
87 %); m.p. 105–107 °C (hexane/AcOEt). IR (film): ν = 1640,
˜
1
1630 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.17–1.19 (m,
6 H, 2 CH3), 2.98 (t, J = 7.0 Hz, 2 H, ArCH2), 3.38–3.41 (m, 4 H,
154 (20), 151 (46), 141 (11), 100 (12), 72 (23). HRMS (CI): calcd. 2 CH2), 3.63 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 4.12 (t, J =
for C20H27N2O3 [MH]+ 343.2022; found 343.2008.
7.0 Hz, 2 H, CH2N), 6.01 (t, J = 3.0 Hz, 1 H, pyrrole H4), 6.23 (s,
1 H, Ar H6), 6.48 (d, J = 3.0 Hz, 1 H, pyrrole H3), 6.50 (d, J =
15.0 Hz, 1 H, HC=CH), 6.53 (d, J = 3.0 Hz, 1 H, pyrrole H5), 7.13
(s, 1 H, Ar H3), 7.61 (d, J = 15.0 Hz, 1 H, HC=CH) ppm. 13C
NMR (75.5 MHz, CDCl3, 25 °C): δ = 13.1, 14.8, 40.7, 41.9, 42.0,
46.6, 55.5, 55.8, 87.5, 108.6, 109.4, 112.6, 112.7, 121.3, 124.8, 129.2,
129.7, 132.6, 148.1, 148.9, 165.7 ppm. MS (CI): m/z (%) = 483 (59)
[MH]+, 482 (2) [M]+, 410 (16), 358 (10), 357 (31), 356 (47), 355
(100), 282 (14), 243 (16), 242 (31), 230 (13), 229 (26), 164 (9).
HRMS (CI): calcd. for C21H28INO3 [MH]+ 483.1145; found
483.1160.
1-(2-Iodo-4,5-dimethoxyphenethyl)-1H-pyrrole-2-carbaldehyde (6a):
1H-Pyrrol-2-carbaldehyde (169 mg, 1.74 mmol) was added over a
suspension of KOH (230 mg, 3.48 mmol) in DMSO (10 mL) at
room temperature, and the reaction mixture was stirred for 2 h.
Then, tosylate 5a[14b] (967 mg, 2.1 mmol) was added, and the re-
sulting reaction mixture was stirred at room temperature for 4 h.
The reaction was quenched by the addition of H2O (20 mL). The
aqueous phase was extracted with CH2Cl2 (3ϫ20 mL), and the
combined organic extracts were washed with H2O (3ϫ20 mL),
dried with Na2SO4, and concentrated in vacuo. Flash column
chromatography (silica gel, 70% hexane/AcOEt) of the resulting
residue afforded 6a as a white solid that was crystallized from hex-
ane/AcOEt (467 mg, 70%); m.p. 88–90 °C (hexane/AcOEt). IR
(E)-N,N-Diethyl-3-{1-[3-(2-iodo-4,5-dimethoxyphenyl)propyl]-1H-
pyrrol-2-yl}acrylamide (7b): N,N-Diethyl-2-(triphenylphosphor-
anylidene)acetamide (2.10 g, 5.59 mmol) was added in portions to
a refluxing solution of N-phenethylpyrrole-2-carbaldehyde (6b)
(1.11 g, 2.79 mmol) in CH2Cl2 (20 mL) over a 2 d period. The crude
reaction mixture was washed with H2O (3ϫ20 mL), dried with
Na2SO4, and concentrated in vacuo. Flash column chromatography
(silica gel, 40% hexane/AcOEt) of the resulting residue afforded 7b
(film): ν = 1660 cm–1. 1H NMR (300 MHz, CDCl , 25 °C): δ = 3.02
˜
3
(t, J = 7.0 Hz, 2 H, ArCH2), 3.63 (s, 3 H, OCH3), 3.74 (s, 3 H,
OCH3), 4.40 (t, J = 7.0 Hz, 2 H, CH2N), 6.06 (dd, J = 4.0, 2.5 Hz,
1 H, pyrrole H4), 6.38 (s, 1 H, Ar H6), 6.58–6.61 (m, 1 H, pyrrole
H3), 6.87 (dd, J = 4.0, 1.5 Hz, 1 H, pyrrole H5), 7.13 (s, 1 H,
Ar H3), 9.51 (s, 1 H, CHO) ppm. 13C NMR (75.5 MHz, CDCl3,
25 °C): δ = 41.4, 48.7, 55.4, 55.8, 87.6, 109.1, 112.7, 121.0, 124.7,
130.7, 131.6, 132.7, 147.9, 148.9, 178.9 ppm. MS (CI): m/z (%) =
386 (12) [MH]+, 385 (17) [M]+, 290 (23), 277 (10), 259 (100), 243
(13), 258 (48), 230 (59), 164 (30). HRMS (CI): calcd. for
C15H17INO3 [MH]+ 386.0253; found 386.0247.
(1.12 g, 81 %) as an oil. IR (film): ν = 1690 cm–1 1H NMR
.
˜
(300 MHz, CDCl3, 25 °C): δ = 1.14–1.24 (m, 6 H, 2 CH3), 1.93–
2.03 (m, 2 H, ArCH2CH2CH2N), 2.59 (t, J = 7.8 Hz, 2 H, ArCH2),
3.39–3.44 (m, 4 H, 2 CH2CH3), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 4.01–4.07 (m, 2 H, CH2N), 6.14 (t, J = 2.5 Hz, 1 H, pyrrole
H4), 6.56 (d, J = 15.0 Hz, 1 H, HC=CH), 6.59–6.61 (m, 1 H, pyr-
role H3), 6.63 (s, 1 H, Ar H6), 6.75 (dd, J = 2.5, 1.6 Hz, 1 H, pyrrole
H5), 7.15 (s, 1 H, Ar H3), 7.65 (d, J = 15.0 Hz, 1 H, HC=CH) ppm.
13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 13.3, 15.1, 32.3, 37.6,
41.1, 42.1, 46.5, 55.9, 56.1, 87.8, 109.0, 109.6, 112.0, 113.0, 121.7,
124.7, 129.6, 130.1, 135.9, 147.9, 149.3, 166.1 ppm. MS (CI): m/z
(%) = 497 (85) [MH]+, 496 (36) [M]+, 424 (26), 399 (15), 385 (17),
384 (21), 373 (28), 372 (30), 371 (97), 370 (100), 369 (82), 368 (40),
298 (13), 296 (23), 270 (20), 256 (23), 219 (10). HRMS (CI): calcd.
for C22H30IN2O3 [MH]+ 497.1301; found 497.1300.
1-[3-(2-Iodo-4,5-dimethoxyphenyl)propyl]-1H-pyrrole-2-carb-
aldehyde (6b): 1H-Pyrrol-2-carbaldehyde (370 mg, 3.77 mmol) was
added over a suspension of KOH (490 mg, 7.55 mmol) in DMSO
(10 mL) at room temperature, and the reaction mixture was stirred
for 2 h. Then, mesylate 5b[14b] (1.81 g, 4.53 mmol) was added, and
the resulting mixture was stirred at room temperature for 16 h. The
reaction was quenched by the addition of H2O (20 mL). The aque-
ous phase was extracted with CH2Cl2 (3ϫ20 mL), and the com-
bined organic extracts were washed with H2O (3ϫ20 mL), dried
with Na2SO4, and concentrated in vacuo. Flash column
chromatography (neutral alumina, 70% hexane/AcOEt) of the re-
2-(8,9-Dimethoxy-6,11-dihydro-5H-pyrrolo[1,2-b][3]benzazepin-11-
yl)-N,N-diethylacetamide (8): According to the general procedure
for MesLi-mediated cyclization reactions, 7a (125 mg, 0.25 mmol)
was treated with MesLi (0.51 mmol), which was prepared from
mesityl bromide (0.08 mL, 0.51 mmol) and tBuLi (0.9 m solution
in hexane, 1.15 mL, 1.03 mmol), at –105 °C. The reaction mixture
was stirred for 5 min. After workup, flash column chromatography
(silica gel, 40% hexane/AcOEt) afforded 8 (81 mg, 88%) as a color-
sulting residue afforded 6b (1.11 g, 74%) as an oil. IR (film): ν =
˜
1
1655 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.98–2.08 (m,
2
H, ArCH2CH2CH2N), 2.65 (t,
J
=
7.5 Hz,
2
H,
ArCH2CH2CH2N), 3.82 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 4.38
(t, J = 7.0 Hz, 2 H, ArCH2CH2CH2N), 6.23 (dd, J = 4.0, 2.5 Hz,
1 H, pyrrole H4), 6.70 (s, 1 H, Ar H6), 6.92 (dd, J = 4.0, 1.5 Hz, 1
H, pyrrole H3), 6.96–6.99 (m, 1 H, pyrrole H5), 7.18 (s, 1 H, Ar H3),
9.54 (s, 1 H, CHO) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ
= 31.9, 37.4, 48.6, 55.9, 55.1, 87.8, 109.6, 112.0, 121.7, 124.9, 131.3,
131.4, 136.1, 147.9, 148.4, 179.3 ppm. MS (CI): m/z (%) = 400 (13)
[MH]+, 399 (55) [M]+, 274 (27), 273 (100), 272 (19), 271 (12), 258
(9), 257 (9), 244 (22), 109 (14). HRMS (CI): calcd. for C16H19INO3
[MH]+ 400.0410; found 400.0394.
less oil. IR (film): ν = 1635 cm–1. 1H NMR (300 MHz, CDCl3,
˜
25 °C): δ = 0.99–1.05 (m, 6 H, 2 CH3), 2.88–2.98 (m, 2 H,
CH2CONEt2), 3.05–3.11 (m, 2 H, CH2), 3.14–3.27 (m, 2 H, 2 H6),
3.28–3.36 (m, 2 H, CH2), 3.82 (s, 6 H, 2 OCH3), 4.19–4.33 (m, 2
H, 2 H5), 4.86 (t, J = 7.4 Hz, 1 H, H11), 5.95 (dd, J = 3.0, 2.0 Hz,
1 H, H1), 6.01 (t, J = 3.0 Hz, 1 H, H2), 6.48–6.51 (m, 1 H, H3),
6.62 (s, 1 H, H10), 6.79 (s, 1 H, H7) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C): δ = 12.9, 14.2, 33.4, 40.3, 40.4, 40.7, 41.8, 48.3,
55.9, 107.0, 107.2, 112.5, 113.1, 121.7, 129.7, 132.7, 133.0, 147.3,
147.4, 170.1 ppm. MS (CI): m/z (%) = 357 (15) [MH]+, 356 (18)
[M]+, 243 (20), 242 (100), 116 (10). HRMS (CI): calcd. for
C21H29N2O3 [MH]+ 357.2178; found 357.2190.
(E)-N,N-Diethyl-3-{[1-(2-iodo-4,5-dimethoxyphenethyl)-1H-pyrrol-
2-yl]}acrylamide (7a): N,N-Diethyl-2-(triphenylphosphoranyl-
idene)acetamide (6.24 g, 16.64 mmol) was added in portions to a
refluxing solution of N-phenethylpyrrole-2-carbaldehyde (6a)
(3.20 g, 8.32 mmol) in CH2Cl2 (20 mL) over a 2 d period. The crude
2-(9,10-Dimethoxy-5,6,7,12-tetrahydropyrrolo[1,2-b][3]benzazocin-
reaction mixture was washed with H2O (3 ϫ20 mL), dried with 12-yl)-N,N-diethylacetamide (9): According to the general pro-
1466 Eur. J. Org. Chem. 2013, 1460–1470
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Intramolecular Carbolithiation
cedure for MesLi-mediated cyclization reactions, 7b (102 mg,
0.20 mmol) was treated with MesLi (0.41 mmol), which was pre-
pared from mesityl bromide (0.064 mL, 0.41 mmol) and tBuLi
(0.95 m solution in hexane, 0.87 mL, 0.82 mmol), at –78 °C. In this
case, TMEDA (0.06 mL, 0.41 mmol) was added, and the mixture
was stirred at this temperature for 5 min. After workup, preparative
thin layer chromatography (silica gel, 90 % CH2Cl2/AcOEt) af-
Trifluoroacetate Salt of (–)-(S,E)-N-Methoxy-N-methyl-3-(pyrrol-
idin-2-yl)acrylamide (11b): N-Methoxy-N-methyl-2-(triphenylphos-
phoranylidene)acetamide (1.56 g, 4.20 mmol) was added in por-
tions to a solution of (S)-N-Boc-prolinal (10, 0.41 g, 2.10 mmol)
in CH2Cl2 (20 mL), and the reaction mixture was stirred at room
temperature overnight. Water was added (10 mL), and the aqueous
layer was extracted with CH2Cl2 (2ϫ20 mL). The combined or-
ganic extracts were washed with H2O (2ϫ10 mL) and saturated
NaCl solution (2ϫ10 mL), dried with Na2SO4, and evaporated un-
forded 9 (32 mg, 42%) as a colorless oil. IR (film): ν = 1680 cm–1.
˜
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.02 (t, J = 7.0 Hz, 3 H,
CH3), 1.22–1.33 (m, 3 H, CH3), 1.56–1.63 (m, 1 H, H6a), 2.19– der reduced pressure. The crude product was purified by flash col-
2.24 (m, 1 H, H6b), 2.84–2.87 (m, 1 H, H7a), 3.17–3.19 (m, 2 H,
umn chromatography (neutral alumina, 50 % hexane/AcOEt) to
give (–)-(S,E)-N-methoxy-N-methyl-3-[(1-tert-butoxycarbonyl)pyr-
CH2CONEt2), 3.26–3.48 (m, 5 H, 2 CH2, H7b), 3.77 (s, 3 H,
OCH3), 3.82 (s, 3 H, OCH3), 3.94–4.10 (m, 1 H, H5a), 4.31–4.35 rolidin-2-yl]acrylamide (570 mg, 96%) as an oil; [α]2D0 = –63.7 (c =
(m, 1 H, H5b), 4.90 (t, J = 7.1 Hz, 1 H, H12), 5.84–5.99 (m, 2 H,
H1, H2), 6.31–6.41 (m, 1 H, H3), 6.54 (s, 1 H, H8), 6.68 (s, 1 H, CDCl3, 25 °C): δ = 1.17 (s, 9 H, tBu), 1.47–1.67 (m, 3 H, 2 H4,
H11) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 13.0, 14.5, H3a), 1.72–1.94 (m, 1 H, H3b), 2.98 (s, 3 H, NCH3), 3.06–3.29 (m,
32.1, 33.9, 35.5, 35.6, 40.1, 41.6, 50.6, 55.9, 56.0, 102.4, 106.5, 2 H, 2 H5), 3.43 (s, 3 H, OCH3), 4.10–4.35 (m, 1 H, H2), 6.15
1.1, CH Cl ). IR (film): ν = 1695 cm–1 1H NMR (300 MHz,
.
˜
2 2
108.5, 113.9, 120.8, 132.1, 135.8, 138.1, 146.9, 147.6, 169.6 ppm.
MS (CI): m/z (%) = 371 (88) [MH]+, 370 (72) [M]+, 284 (11), 270
(19), 269 (13), 258 (14), 257 (26), 256 (100). HRMS (CI): calcd. for
C22H31N2O3 [MH]+ 371.2335; found 371.2348.
(d, J = 15.0 Hz, 1 H, HC=CH), 6.55 (dd, J = 15.0, 4.4 Hz, 1 H,
HC=CH) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C, rotamers): δ
= 13.6, 27.8, 20.3, 31.7, 45.6, 57.5, 59.6, 61.1, 78.7, 117.3, 117.7,
145.5, 146.5, 165.9, 170.2 ppm. MS (CI): m/z (%) = 285 (8)
[MH]+, 229 (100), 224 (7), 196 (11), 95 (7). C14H24N2O4 (284.35):
calcd. C 59.13, H 8.51, N 9.85; found C 59.48, H 8.25, N 9.43. A
solution of this N-Boc-2-substituted pyrrolidine (210 mg,
0.75 mmol) in CH2Cl2 (20 mL) was treated with TFA (0.30 mL,
3.73 mmol), and the mixture was stirred overnight at room tem-
perature. Evaporation of the solvent under reduced pressure af-
forded 11b as an oil; [α]2D0 = –10.4 (c = 1, CH2Cl2). To obtain the
free amine of 11b, a CH2Cl2 solution of crude trifluoroacetate 11b
was washed with aqueous 10% NaOH solution (2ϫ10 mL) and
dried, followed by evaporation of the solvent (120 mg, 87%). IR
nBuLi/(–)-Sparteine-Mediated Cyclization of 2d for the Synthesis of
Enantioenriched (–)-3d: nBuLi (1.1 m solution in hexane, 0.4 mL,
0.43 mmol) was added to a solution of (–)-sparteine (0.1 mL,
0.43 mmol) in dry toluene (5 mL) at –78 °C, and the reaction mix-
ture was stirred at this temperature for 10 min. The solution was
cooled to –90 °C, and a solution of N-(o-iodobenzyl)pyrrole 2d
(136 mg, 0.29 mmol) in dry toluene (5 mL) was added dropwise.
The reaction mixture was stirred for 5 min and then was quenched
by the addition of a saturated NH4Cl solution (10 mL). Et2O
(15 mL) was added, and the organic layer was separated. The aque-
ous phase was extracted with CH2Cl2 (3ϫ15 mL). The combined
organic extracts were dried with Na2SO4 and concentrated in
vacuo. Flash column chromatography (silica gel, 60% hexane/Ac-
OEt) of the resulting residue afforded 3d (60 mg, 70%) as a color-
less oil. The spectroscopic data were identical to those of the race-
mic mixture. [α]2D0 = –0.31 (c = 1, CH2Cl2). The enantiomeric excess
value of 3d was determined by HPLC to be 37%. HPLC (Chiralcel
OD, 10% hexane/2-propanol, 0.6 mL/min): tR = 23.6 min (68.5%),
tR = 30.2 min (31.5%).
(film): ν = 1695 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
˜
1.41–1.48 (m, 1 H, H3a), 1.63–1.78 (m, 2 H, 2 H4), 1.87–1.94 (m, 1
H, H3a), 2.15 (br. s, 1 H, NH), 2.82–2.87 (m, 1 H, H5a), 2.94–2.99
(m, 1 H, H5b), 3.14 (s, 3 H, NCH3), 3.60 (s, 3 H, OCH3), 3.67 (q,
J = 7.0 Hz, 1 H, H2), 6.43 (d, J = 15.4 Hz, 1 H, HC=CH), 6.83
(dd, J = 15.4, 7.0 Hz, 1 H, HC=CH) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C): δ = 25.0, 31.7, 46.3, 59.4, 61.5, 117.5, 148.5,
166.6 ppm. MS (CI): m/z (%) = 185 (8) [MH]+, 183 (18), 124 (100),
96 (21). C9H16N2O2 (184.24): calcd. C 58.67, H 8.75, N 15.21;
found C 58.48, H 8.25, N 15.43.
Trifluoroacetate Salt of (–)-(S,E)-N,N-Diethyl-3-(pyrrolidin-2-yl)-
acrylamide (11a): N,N-Diethyl-2-(triphenylphosphoranylidene)-
acetamide (0.9 g, 2.41 mmol) was added in portions to a solution
of (S)-N-Boc (tert-butoxycarbonyl)-prolinal (10, 0.24 g, 1.20 mmol)
(–)-(S,E)-N,N-Diethyl-3-[(4,5-dimethoxy-o-iodobenzyl)pyrrolidin-
2-yl]acrylamide (12a): A solution of pyrrolidinium trifluoroacetate
(11a) (1.00 g, 3.22 mmol) in EtOH (30 mL) was treated with KOH
in CH2Cl2 (20 mL), and the reaction mixture was stirred at room (0.43 g, 6.43 mmol), and the mixture was stirred at room tempera-
temperature overnight. Water was added (10 mL), and the aqueous
layer was extracted with CH2Cl2 (2ϫ20 mL). The combined or-
ganic extracts were washed with H2O (2ϫ10 mL) and saturated
ture for 30 min. 4,5-Dimethoxy-o-iodobenzyl bromide (570 mg,
1.61 mmol) was added, and the resulting solution was stirred at
room temperature for 15 h. The reaction was quenched by the ad-
NaCl solution (2ϫ10 mL), dried with Na2SO4, and evaporated un- dition of water (20 mL), and the aqueous phase was extracted with
der reduced pressure. The crude product was purified by flash col-
umn chromatography (neutral alumina, 50 % hexane/AcOEt) to
give (–)-(S,E)-N,N-diethyl-3-[(1-tert-butoxycarbonyl)pyrrolidin-2-
yl]acrylamide[42] (0.30 g, 84%) as an oil; [α]2D0 = –66.0 (c = 1,
CH2Cl2). A solution of this N-Boc-2-pyrrolidine (0.29 g,
0.97 mmol) in CH2Cl2 (20 mL) was treated with TFA (0.38 mL,
4.85 mmol), and the mixture was stirred overnight at room tem-
perature. Evaporation of the solvent under reduced pressure af-
forded 2-alkenyl pyrrolidine trifluoroacetate 11a as an oil. When
the product was purified by flash column chromatography (neutral
alumina, 50% MeOH/AcOEt), the free amine[42] of 11a was ob-
tained (0.12 g, 65%); [α]2D0 = –10.0 (c = 1.1, CH2Cl2). C11H20N2O
(196.29): calcd. C 67.31, H 10.27, N 14.27; found C 67.78, H 10.21,
N 14.42.
AcOEt (2ϫ20 mL). The combined organic extracts were washed
with brine (20 mL), dried with Na2SO4, and evaporated under re-
duced pressure. The crude product was purified by flash column
chromatography (silica gel, 20 % hexane/AcOEt) to give 12a
(0.55 g, 72%) as an oil; [α]2D0 = –27.4 (c = 1.1, CH2Cl2). IR (film):
1
ν = 1660 cm–1. H NMR (300 MHz, CDCl , 25 °C): δ = 1.10–1.14
˜
3
(m, 6 H, 2 CH3), 1.65–1.84 (m, 3 H, 2 H4, H3a), 1.98–2.04 (m, 1
H, H3b), 2.25 (q, J = 8.5 Hz, 1 H, H5a), 2.99–3.03 (m, 1 H, H5b),
3.16 (q, J = 7.8 Hz, 1 H, H2), 3.28–3.32 (m, 2 H, CH2), 3.30 (d, J
= 14.0 Hz, 1 H, ArCHaHbN), 3.39 (q, J = 7.0 Hz, 2 H, CH2), 3.78
(d, J = 14.0 Hz, 1 H, ArCHaHbN), 3.81 (s, 3 H, OCH3), 3.84 (s, 3
H, OCH3), 6.33 (d, J = 15.0 Hz, 1 H, CH=CHCONEt2), 6.84 (dd,
J = 15.0, 7.8 Hz, 1 H, CH=CHCONEt2), 7.03 (s, 1 H, Ar H3), 7.17
(s, 1 H, Ar H6) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ =
Eur. J. Org. Chem. 2013, 1460–1470
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1467

I. Coldham, E. Lete et al.
FULL PAPER
13.0, 14.8, 22.8, 31.5, 40.7, 42.1, 53.6, 55.9, 56.0, 62.1, 66.4, 87.1,
112.7, 121.2, 134.1, 147.2, 148.3, 149.3, 165.4 ppm. MS (CI): m/z
(%) = 473 (96) [MH]+, 472 (29) [M]+, 471 (26), 345 (23), 277 (100),
195 (75). HRMS (CI): calcd. for C20H30IN2O3 [MH]+ 473.1301;
found 473.1313. C20H29IN2O3 (472.37): calcd. C 50.85, H 6.19, N
5.93; found C 50.41, H 6.25, N 5.98. The enantiomeric excess value
of 12a was determined by HPLC to be Ͼ99%. HPLC (Chiralcel
ASH, 10 % hexane/2-propanol, 0.8 mL/min): tR = 13.28 min
(Ͼ99%, for S enantiomer), tR = 36.99 min (Ͻ1%, for R enanti-
omer).
21.5, 30.2, 38.1, 40.8, 41.0, 42.2, 54.9, 55.7, 55.8, 67.1, 109.3, 110.2,
127.3, 130.8, 147.0, 147.6, 171.2 ppm. MS (CI): m/z (%) = 347 (85)
[MH]+, 346 (8) [M]+, 274 (2), 246 (3), 231 (100). HRMS (CI): calcd.
for C20H31N2O3 [MH]+ 347.2335; found 347.2348. C20H30N2O3
(346.46): calcd. C 69.33, H 8.73, N 8.09; found C 69.53, H 8.04, N
8.57. The enantiomeric excess value of 13a was determined by
HPLC to be Ͼ99%. HPLC (Chiralcel ASH, 10% hexane/2-propa-
nol, 0.8 mL/min): tR = 13.28 min (Ͼ99 %, for 10R,10aS enanti-
omer), tR = 36.99 min (Ͻ1%, for 10S,10aR enantiomer).
(+)-2-[(10R,10aS)-7,8-Dimethoxy-1,2,3,5,10,10a-hexahydropyr-
rolo[1,2-b]isoquinolin-10-yl]-N-methoxy-N-methylacetamide (13b):
nBuLi (1.04 m solution in hexanes, 0.47 mL, 0.48 mmol) and
TMEDA (0.07 mL, 0.48 mmol) were added sequentially to a solu-
tion of 12b (100 mg, 0.22 mmol) in dry THF (10 mL) at –78 °C.
After 10 min, the reaction was quenched by the addition of a satu-
rated NH4Cl solution (10 mL). The organic layer was separated,
and the aqueous phase was extracted with Et2O (10 mL) and then
CH2Cl2 (2ϫ10 mL). The combined organic extracts were dried
with Na2SO4 and evaporated under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
(–)-(S,E)-N-Methoxy-N-methyl-3-[(4,5-dimethoxy-o-iodobenzyl)pyr-
rolidin-2-yl]acrylamide (12b): A solution of pyrrolidinium trifluo-
roacetate 11b (800 mg, 2.69 mmol) in EtOH (30 mL) was treated
with KOH (0.36 g, 5.38 mmol), and the mixture was stirred at room
temperature for 30 min. 4,5-Dimethoxy-o-iodobenzyl bromide
(480 mg, 1.35 mmol) was added, and the resulting solution was
stirred at room temperature for 15 h. The reaction was quenched
by the addition of water (20 mL), and the aqueous phase was ex-
tracted with AcOEt (2ϫ20 mL). The combined organic extracts
were washed with brine (20 mL), dried with Na2SO4, and evapo-
rated under reduced pressure. The crude product was purified by
flash column chromatography (silica gel, 80% hexane/AcOEt) to
50% AcOEt/MeOH) to give 13b (42 mg, 58%) as an oil; [α]2D0
+5.4 (c = 1, CH Cl ). IR (film): ν = 1651 cm–1 1H NMR
=
.
˜
2
2
give 12b (0.51 g, 82%) as an oil; [α]2D0 = –23.1 (c = 1.1, CH2Cl2).
(300 MHz, CDCl3, 25 °C): δ = 1.60–1.68 (m, 1 H, H1a), 1.75–1.94
(m, 2 H, 2 H2), 2.00–2.14 (m, 2 H, H1b, CHaHbCO), 2.18–2.32 (m,
3 H, 2 H3, H10a), 2.78 (t, J = 6.7 Hz, 1 H, CHaHbCO), 3.19–3.27
(m, 1 H, H10), 3.22 (s, 3 H, NCH3), 3.45 (d, J = 14.0 Hz, 1 H, H5a),
3.68 (s, 3 H, NOCH3), 3.82 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3),
3.97 (d, J = 14.0 Hz, 1 H, H5b), 6.54 (s, 1 H, H6), 6.77 (s, 1 H,
H9) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 21.5, 30.2,
36.4, 40.8, 54.8, 55.7, 55.8, 55.9, 61.4, 66.7, 109.4, 110.1, 127.3,
130.3, 147.1, 147.6, 173.8 ppm. MS (CI): m/z (%) = 335 (100)
[MH]+, 334 (10) [M]+, 333 (18), 303 (58), 231 (9). HRMS (CI):
calcd for C18H27N2O4 [MH]+ 335.1971; found 335.1984.
C18H26N2O4 (334.41): calcd. C 64.65, H 7.84, N 8.38; found C
64.57, H 8.19, N 8.02. The enantiomeric excess value of 13b was
determined by HPLC to be Ͼ99%. HPLC (Chiralcel ASH, 10%
hexane/2-propanol, 0.8 mL/min): tR = 17.21 min (Ͼ 99%, for
10R,10aS enantiomer), tR = 45.00 min (Ͻ1%, for 10S,10aR enanti-
omer).
1
IR (film): ν = 1670 cm–1. H NMR (300 MHz, CDCl , 25 °C): δ =
˜
3
1.65–1.88 (m, 3 H, 2 H4, H3a), 2.01–2.07 (m, 1 H, H3b), 2.28 (q, J
= 9.0 Hz, 1 H, H5a), 2.98–3.06 (m, 1 H, H5b), 3.20–3.24 (m, 1 H,
H2), 3.23 (s, 3 H, NCH3), 3.34 (d, J = 14.0 Hz, 1 H, ArCHaHbN),
3.65 (s, 3 H, OCH3), 3.80 (d, J = 14.0 Hz, 1 H, ArCHaHbN), 3.84
(s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 6.56 (d, J = 15.5 Hz, 1 H,
CH=CHCO), 6.95 (dd, J = 15.5, 8.0 Hz, 1 H, CH=CHCO), 7.04
(s, 1 H, Ar H3), 7.19 (s, 1 H, Ar H6) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C): δ = 22.9, 31.6, 53.7, 56.0, 56.1, 61.7, 62.1, 66.3,
87.3, 112.9, 119.2, 121.4, 134.2, 148.4, 149.1, 149.4, 166.6 ppm. MS
(CI): m/z (%) = 461 (37) [MH]+, 460 (4) [M]+, 431 (26), 430 (19),
277 (100). HRMS (CI): calcd. for C18H26IN2O4 [MH]+ 461.0937;
found 461.0954. C18H25IN2O4 (460.31): calcd. C 46.97, H 5.47, N
6.09; found C 47.41, H 5.46, N 5.49. The enantiomeric excess value
of 12b was determined by HPLC to be Ͼ99%. HPLC (Chiralcel
ASH, 10 % hexane/2-propanol, 0.8 mL/min): tR = 17.23 min
(Ͼ99%, for S enantiomer), tR = 44.52 min (Ͻ1%, for R enanti-
omer).
Supporting Information (see footnote on the first page of this arti-
cle): Isolation and characterization of byproducts in the tBuLi-me-
1
diated cyclization of 2a–2d, copies of H and 13C NMR spectra of
(+)-2-[(10R,10aS)-7,8-Dimethoxy-1,2,3,5,10,10a-hexahydropyr-
rolo[1,2-b]isoquinolin-10-yl]-N,N-diethylacetamide (13a): nBuLi
(1.16 m solution in hexanes, 0.41 mL, 0.41 mmol) and TMEDA
(0.06 mL, 0.41 mmol) were added sequentially to a solution of 12a
(90 mg, 0.19 mmol) in dry THF (10 mL) at –78 °C. After 10 min,
the reaction was quenched by the addition of a saturated NH4Cl
solution (10 mL). The organic layer was separated, and the aque-
ous phase was extracted with Et2O (10 mL) and then CH2Cl2
compounds described, and CSP (chiral stationary phase) HPLC
chromatograms of 12a, 12b, 13a, and 13b.
Acknowledgments
We wish to thank the Ministerio de Ciencia e Innovación (MIC-
(2 ϫ 10 mL). The combined organic extracts were dried with INN) (CTQ2009-07733), the University of Sheffield, and the Uni-
Na2SO4 and evaporated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, 50% Ac-
OEt/MeOH) to give 13a (40 mg, 60%) as an oil; [α]2D0 = +5.8 (c =
versidad del País Vasco/Euskal Herriko Unibertsitatea (UFI11/22
and GIU 0946) for their financial support. Technical and human
support provided by the Servicios Generales de Investigación
SGIker (UPV/EHU, MICINN, GV/EJ, ERDF, and ESF) are grate-
fully acknowledged. We also thank Gobierno Vasco for a grant
(E. C.).
1, CH Cl ). IR (film): ν = 1650 cm–1. 1H NMR (300 MHz, CDCl ,
˜
2
2
3
25 °C): δ = 1.16 (t, J = 7.1 Hz, 6 H, 2 CH3), 1.64–1.72 (m, 1 H,
H1a), 1.75–1.81 (m, 1 H, H2a), 1.85–1.94 (m, 1 H, H2b), 2.02–2.08
(m, 1 H, H1b), 2.11–2.20 (m, 1 H, H10a), 2.26–2.35 (m, 1 H, H3a),
2.52 (dd, J = 15.5, 6.5 Hz, 1 H, CHaHbCO), 2.64 (dd, J = 15.5,
6.5 Hz, 1 H, CHaHbCO), 3.22 (td, J = 8.8, 1.7 Hz, 1 H, H3b), 3.31–
3.39 (m, 3 H, H5a, CH2CH3), 3.44 (q, J = 7.1 Hz, 2 H, CH2CH3),
3.45–3.51 (m, 1 H, H10), 3.78 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3),
3.96 (d, J = 14.0 Hz, 1 H, H5b), 6.52 (s, 1 H, H6), 6.73 (s, 1 H,
H9) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 13.1, 14.6,
[1] For general reviews on isolation, synthesis and biological ac-
tivity of Amaryllidaceae alkaloids, see: a) O. Hoshino, in: The
Alkaloids (Ed.: G. A Cordell), Academic Press, San Diego,
1998, vol. 51, pp. 324–424; b) A. Kornienko, A. Evidente,
Chem. Rev. 2008, 108, 1982–2014; also, see: Z. Jin, Nat. Prod.
Rep. 2011, 28, 1126–1142.
1468
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1460–1470

Intramolecular Carbolithiation
[2]
335; c) M. J. Mealy, W. F. Bailey, J. Organomet. Chem. 2002,
646, 59–67; d) J. F. Normant, Top. Organomet. Chem. 2003,
287–310; e) F. J. Fañanás, R. Sanz, in: The Chemistry of
Organolithium Compounds, Patai Series: The Chemistry of
Functional Groups (Eds.: Z. Rappoport, I. Marek), Wiley,
Chichester, UK, 2006, vol. 2, pp. 295–379; f) A. M. L. Hogan,
D. F. O’Shea, Chem. Commun. 2008, 3839–3851; g) U. Martí-
nez-Estíbalez, A. Gómez-Sanjuán, O. García-Calvo, S. Ar-
rasate, N. Sotomayor, E. Lete, in: Targets in Heterocyclic Sys-
tems (Eds.: O. Attanasi, D. Spinelli), Italian Society of Chemis-
try, Rome, 2010, vol. 14, pp. 124–149; h) N. Sotomayor, E. Lete,
in: Science of Synthesis Knowledge Updates 2011/4 (Eds.: D. G.
Hall, K. Ishikara, J. J. Li, I. Marek, M. North, E. Schaumann,
S. M. Weinreb, M. Yus), Thieme, Stuttgart, Germany, 2011, pp.
191–251.
For selected examples, see: a) A. Krief, B. Remacle, J. Mercier,
Synlett 2000, 1443–1446; b) K. Deng, A. Bensari, T. Cohen, J.
Am. Chem. Soc. 2002, 124, 12106–12107; c) W. F. Bailey, T.
Daskapan, S. Rampalli, J. Org. Chem. 2003, 68, 1334–1338; d)
R. Ortiz, M. Yus, Tetrahedron 2005, 61, 1699–1707; e) K. Deng,
A. Bensari-Bouguerra, J. Whetstone, T. Cohen, J. Org. Chem.
2006, 71, 2360–2372; f) T. Liu, X. Zhao, L. Lu, T. Cohen, Org.
Lett. 2009, 11, 4576–4579.
For selected examples, see: a) F. J. Fañanás, A. Granados, R.
Sanz, J. M. Ignacio, J. Barluenga, Chem. Eur. J. 2001, 7, 2896–
2907; b) J. Barluenga, F. J. Fañanás, R. Sanz, J. M. Ignacio,
Eur. J. Org. Chem. 2003, 771–783; c) I. Coldham, K. N. Price,
R. E. Rathmell, Org. Biomol. Chem. 2003, 1, 2111–2119; d) G.
Christoph, C. Stratmann, I. Coldham, D. Hoppe, Org. Lett.
2006, 8, 4469–4471; e) W. F. Bailey, P. D. Salgaonkar, J. D. Bru-
baker, V. Sharma, Org. Lett. 2008, 10, 1071–1074.
R. Pedrosa, C. Andrés, J. M. Iglesias, A. Pérez-Encabo, J. Am.
Chem. Soc. 2001, 123, 1817–1821.
I. Coldham, R. Hufton, K. N. Price, R. E. Rathmell, D. J.
Snowden, G. P. Vennall, Synthesis 2001, 1523–1531.
a) I. Coldham, G. P. Vennall, Chem. Commun. 2000, 1569–
1570; b) N. J. Ashweek, I. Coldham, D. J. Snowden, G. P. Ven-
nall, Chem. Eur. J. 2002, 8, 195–207.
For selected reviews on the therapeutic potential of these alka-
loids (and their synthetic analogues) as antitumor agents, see:
a) S. R. Chemler, Curr. Bioact. Compd. 2009, 5, 2–19; b) K.-H.
Lee, J. Nat. Prod. 2010, 73, 500–516; for general reviews on
isolation, synthesis and biological activity, see: c) J. P. Michael,
Nat. Prod. Rep. 2008, 25, 139–165; d) Z. Li, Z. Jin, R. Huang,
Synthesis 2001, 2365–2378.
For example, see: a) A. Couture, E. Deniau, P. Grandclaudon,
S. Lebrun, S. Leonce, P. Renard, B. Pfeiffer, Bioorg. Med.
Chem. 2000, 8, 2113–2125; b) R. Chaniyara, N. Kapuriya, H.
Dong, P. C. Lee, S. Suman, B. Marvania, T.-C. Chou, T.-C.
Lee, R. Kakadiya, A. Shah, T.-L. Su, Bioorg. Med. Chem. 2011,
19, 275–286.
a) S. Zhao, M. J. Totleben, J. P. Freeman, C. L. Bacon, G. B.
Fox, E. O’Driscoll, A. G. Foley, J. Kelly, U. Farrell, C. Regan,
S. A. Mizsak, J. Szmuszkovicz, Bioorg. Med. Chem. 1999, 7,
1637–1646; b) J. Szmuszkovicz, C. M. Regan, PCT Int. Patent
Appl. WO 2000004905 A1 20000203, 2000 [available through
Espacenet Portal http://www.espacenet.com accessed February
22, 2012]; for a review on acetylcholinesterase inhibitors in the
context of therapeutic strategies to combat Alzheimer’s disease,
see: c) M. Recanatini, A. Cavalli, Expert Opin. Ther. Pat. 2002,
12, 1853–1865.
For general reviews on isolation, synthesis and pharmacologi-
cal and clinical studies of Cephalotaxus alkaloids, see: M. A. J.
Miah, T. Hudlicky, J. W. Reed, in: The Alkaloids (Ed.: G. A.
Cordell), Academic Press, San Diego, 1998, vol. 51, pp. 199–
269.
[3]
[4]
[16]
[17]
[5]
[6]
[7]
For a recent review on their antileukemic activity, see: A.
Quintás-Cardama, H. Kantarjian, J. Cortes, Cancer 2009,
5382–5393.
[18]
[19]
[20]
a) D. C. Remy, S. F. Britcher, S. W. King, P. S. Anderson, P.
Belanger, J. G. Atkinson, Y. Girard, B. V. Clineschmidt, J. Med.
Chem. 1983, 26, 974–980; b) G. Campiani, S. Butini, C. Fatto-
russo, F. Trotta, S. Gemma, B. Catalanotti, V. Nacci, I. Fiorini,
A. Cagnotto, I. Mereghetti, T. Mennini, P. Minetti, M. A.
Di Cesare, M. A. Stasi, S. Di Serio, O. Ghirardi, O. Tinti, P.
Carminati, J. Med. Chem. 2005, 48, 1705–1708; c) S. Avram,
H. Berner, A. L. Milac, P. Wolschann, Monatsh. Chem. 2008,
139, 407–426.
For the classic Weinreb synthesis of cephalotaxine, see: J. Auer-
bach, S. M. Weinreb, J. Am. Chem. Soc. 1972, 94, 7172–7173;
for related synthetic procedures, for example, see: Y. Koseki,
H. Sato, Y. Watanabe, T. Nagasaka, Org. Lett. 2002, 4, 885–
888, and references cited therein.
For isolation and characterization, see: a) F. Viladomat, J. Bas-
tida, C. Codina, W. E. Campbell, S. Mathee, Phytochemistry
1995, 40, 307–311; for representative examples of syntheses,
see: b) C. Hoarau, A. Couture, E. Deniau, P. Grandclaudon,
J. Org. Chem. 2002, 67, 5846–5849; c) S. Kodama, H. Takita,
T. Kajimoto, K. Nishide, M. Node, Tetrahedron 2004, 60,
4901–4907; d) P. Appukkuttan, W. Dehaen, E. Van der Eycken,
Chem. Eur. J. 2007, 13, 6452–6460.
I. Conte, C. Ercolani, F. Narjes, M. Pompei, M. Rowley, I.
Stansfield, PCT Int. Patent Appl. WO 2006046030 A2
20060504 2006 [available through Espacenet Portal http://
www.espacenet.com accessed February 22, 2012].
[21]
[22]
[23]
[24]
[25]
U. Martínez-Estíbalez, N. Sotomayor, E. Lete, Org. Lett. 2009,
11, 1237–1240.
S. Lage, I. Villaluenga, N. Sotomayor, E. Lete, Synlett 2008,
3188–3192.
S. Lage, U. Martínez-Estíbalez, N. Sotomayor, E. Lete, Adv.
Synth. Catal. 2009, 351, 2460–2468.
[8]
[9]
W. F. Bailey, M. J. Mealy, K. B. Wiberg, Org. Lett. 2002, 4,
791–794.
For the effect of the addition of a bidentate ligand such as
TMEDA to facilitate and accelerate the rate of carbolithiation
reactions, for instance, see: a) W. F. Bailey, X.-L. Jiang, C. E.
McLeod, J. Org. Chem. 1995, 60, 7791–7795; b) I. Coldham,
J. C. Fernández, K. N. Price, D. J. Snowden, J. Org. Chem.
2000, 65, 3788–3795; c) R. Sanz, J. M. Ignacio, M. A. Rodrig-
uez, F. J. Fañanás, J. Barluenga, Chem. Eur. J. 2007, 13, 4998–
5008.
[10]
[26]
[27]
M. Yus, R. Ortiz, Eur. J. Org. Chem. 2004, 3833–3841.
W. F. Bailey, T. Daskapan, S. Rampalli, J. Org. Chem. 2003,
68, 1334–1338.
[11]
[12]
K. C. Majumdar, RSC Adv. 2011, 1, 1152–1170.
K. C. Majumdar, B. Chattopadhyay, Curr. Org. Chem. 2009,
13, 731–757.
[28]
[29]
S. B. Mhaske, Synlett 2005, 184–185.
a) A. K. Beck, M. S. Hoekstra, D. Seebach, Tetrahedron Lett.
1977, 18, 1187–1190; b) M. Yoshifuji, T. Nakamura, N. Inam-
oto, Y. Yamamoto, Tetrahedron Lett. 1987, 28, 6325–6328; c)
Y. Yamamoto, K. Maeda, K. Tomimoto, T. Mase, Synlett 2002,
561–564.
a) D. L. Comins, S. Huang, C. L. McArdale, C. L. Ingalls, Org.
Lett. 2001, 3, 469–471; b) D. L. Comins, J. M. Nolan, Org.
Lett. 2001, 3, 4255–4257; c) S. B. Mhaske, N. P. Argade, J. Org.
Chem. 2004, 69, 4563–4566; d) H. Naka, Y. Akagi, K. Yamada,
T. Imahori, T. Kasahara, Y. Kondo, Eur. J. Org. Chem. 2007,
4635–4637; e) D. L. Comins, P. W. Odachi, Tetrahedron Lett.
2008, 49, 569–572.
[13]
[14]
U. Martínez-Estíbalez, A. Gómez-Sanjuan, O. García-Calvo,
E. Aranzamendi, E. Lete, N. Sotomayor, Eur. J. Org. Chem.
2011, 3610–3633.
a) J. Ruiz, N. Sotomayor, E. Lete, Org. Lett. 2003, 5, 1115–
117; b) J. Ruiz, A. Ardeo, R. Ignacio, N. Sotomayor, E. Lete,
Tetrahedron 2005, 61, 3311–3324; c) J. Ruiz, N. Sotomayor, E.
Lete, Tetrahedron 2006, 62, 6182–6189.
For selected reviews, see: a) I. Marek, J. Chem. Soc. Perkin
Trans. 1 1999, 535–544; b) J. Clayden, Organolithiums: Selectiv-
ity for Synthesis Pergamon Press, New York, 2002, pp. 282–
[30]
[15]
Eur. J. Org. Chem. 2013, 1460–1470
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1469

I. Coldham, E. Lete et al.
FULL PAPER
[31]
[36] The reactions with MesLi did not give better results. In view
of the low ee obtained, no efforts were made to determine the
absolute configuration.
[37] O. García-Calvo, N. Sotomayor, E. Lete, I. Coldham, ARKI-
VOC (Gainesville, FL, U. S.) 2011, 5, 57–66.
[38] The enantiomeric purity was checked by using chiral stationary
phase HPLC and comparing the data with those obtained from
the racemic samples, which were prepared by following the
same procedures, but starting with racemic 10; see Exp. Section
and Supporting Information
Y. Kondo, M. Asai, T. Miura, M. Uchiyama, T. Sakamoto,
Org. Lett. 2001, 3, 13–15.
As described in ref.[14b], 5a and 5b were prepared from the cor-
[32]
responding alcohols.
1
[33] The yield was calculated by integrating the corresponding H
NMR signals with respect to the alkene protons of the deiodin-
ated starting material, which was observed as a byproduct.
[34] For reviews on the use of (–)-sparteine as a chiral ligand, see:
a) P. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer, D. J.
Pippel, G. A. Weisenburger, Acc. Chem. Res. 2000, 33, 715–727;
b) D. Hoppe, G. Christoph, in: The Chemistry of Organolithium
Compounds, Patai Series: The Chemistry of Functional Groups
(Eds.: Z. Rappoport, I. Marek), John Wiley & Sons, New York,
2004, pp. 1055–1164.
[35] a) D. Hoppe, M. J. Woltering, M. Oestrich, R. Frölich, Helv.
Chim. Acta 1999, 82, 1860–1877; b) W. F. Bailey, M. J. Mealy,
J. Am. Chem. Soc. 2000, 122, 6787–6788; c) G. Sanz, U. M.
Groth, J. Am. Chem. Soc. 2000, 122, 6789–6790; d) J. Bar-
luenga, F. J. Fañanás, R. Sanz, C. Marcos, Org. Lett. 2002, 4,
2225–2228; e) M. J. Mealy, M. R. Luderer, W. F. Bailey, M. B.
Sommer, J. Org. Chem. 2004, 69, 6042–6049; f) J. Barluenga,
F. J. Fañanás, R. Sanz, C. Marcos, Chem. Eur. J. 2005, 11,
5397–5407; g) U. Groth, P. Köttgen, P. Langenbach, A. Lin-
denmaier, T. Schütz, M. Wiegand, Synlett 2008, 1301–1304.
[39] S. Arrasate, E. Lete, N. Sotomayor, Tetrahedron: Asymmetry
2002, 13, 311–316; also see ref.[21]
.
[40] NOESY and COSY experiments confirmed the stereochemis-
try of 13a and 13b. In particular, 2D NOESY experiments
showed an enhancement between protons H-10 and H-1 and
between H-10a and the methylenic protons of the substituent
at C-10. These data are consistent with a trans stereochemistry
in the indolizidine system.
[41] a) D. D. Perrin, W. L. F. Armarego, Purification of Laboratory
Chemicals, 4th ed., Pergamon Press, Oxford, 1997; b) D. B. G.
Williams, M. Lawton, J. Org. Chem. 2010, 75, 8351–8354.
[42] The spectroscopic data were identical to those described for
the racemic mixture. See ref.[37]
.
Received: July 25, 2012
Published Online: November 6, 2012
1470
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1460–1470