A copper-catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a] isoquinolines

Article abstract of DOI:10.1002/anie.200804427

(Chemical Equation Presented) Isoquinoline ring the changes: A novel strategy for the title reaction involves ortho-haloarylalkynes which undergo sequential intermolecular addition of N heterocycles onto alkynes and subsequent intramolecular ring closure by arylation. The process involves the use of hydroxymethyl benzotriazole as an efficient and inexpensive ligand for the C - N and C - C coupling reactions.

Full text of DOI:10.1002/anie.200804427

Communications
DOI: 10.1002/anie.200804427
Heterocycles
A Copper-Catalyzed Tandem Synthesis of Indolo- and
Pyrrolo[2,1-a]isoquinolines**
Akhilesh Kumar Verma,* Tanay Kesharwani, Jaspal Singh, Vibha Tandon, and
Richard C. Larock*
Dedicated to Professor Alan R. Katritzky on the occasion of his 80th birthday
Transition-metal-catalyzed tandem reactions have emerged as
a useful tool for the synthesis of multiring heterocyclic
compounds because of the intriguing selectivity, atom econ-
omy,[1] and exceptional ability to activate p systems, especially
alkynes, towards intermolecular and intramolecular nucleo-
philic attack.[2] Among the transition-metal-catalyzed reac-
tions, palladium is extensively used because of its tolerance of
many functional groups and its low toxicity.[3] However, in
recent years copper-catalyzed reactions have received con-
siderable attention because of their efficiency and low
costs.[2f,4,5] The reported annulation chemistry for the syn-
thesis of heterocycles from alkynes proceeds through p com-
plexation of the alkyne and subsequent attack of the resulting
h2-metal complex onto the appropriate adjacent functional-
ized arene.[2a,6] However, the synthesis of polyheterocycles by
the nucleophilic addition of N heterocycles onto alkynes and
co-workers reported the synthesis of analogous isoquinolines
by the cycloisomerization of biaryl alkynes using PtCl2, AuCl,
AuCl3, GaCl3, or InCl3.[2a] Herein, we report the first copper-
catalyzed synthesis of this class of heterocycles by the tandem
addition of N heterocycles onto alkynes and subsequent
intramolecular cyclization of the in situ generated enamine
by C2 arylation.
In continuation of recently developed methods for the
copper-catalyzed N-arylation using benzotriazole as
a
ligand[13] and the electrophilic cyclization of alkynes,[14,15] we
hypothesized that the direct synthesis of polycyclic hetero-
aromatic compound 6 could occur in a one-pot reaction of
À
N heterocycle 1 with ortho-haloarylalkyne 2 by sequential N
À
C and C C bond formation under the proper conditions such
that intermediate 5 would not have to be isolated (Scheme 1,
route A). We also anticipated the possible formation of
regioisomer 3 by initial arylation of N heterocycle 1 at the C2-
position by the ortho-haloarylalkyne 2 and subsequent intra-
molecular attack of the N heterocycle onto the carbon–
carbon triple bond of the in situ generated intermediate 4
(Scheme 1, route B). This designed tandem reaction features
the use of benzotriazole (L1) and benzotriazol-1-ylmethanol
(L2) as novel and inexpensive ligands in copper-catalyzed
reactions.
À
subsequent in situ ring closure by C C bond formation is still
unknown.
Indolo[2,1-a]isoquinolines and pyrrolo[2,1-a]isoquino-
lines have unique nitrogen-containing tetracyclic and tricyclic
structures, and their reduced and oxidized forms occur widely
among natural products,[7] biologically active pharmaceuti-
cals,[8] and p-conjugated functional materials, such as organic
semiconductors and luminescent materials.[9] The reported
methods for the syntheses of indolo- and pyrrolo[2,1-a]iso-
quinolines, typically require multistep syntheses and expen-
sive reagents.[10,11] Methods for the construction of these
structures include well known benzyne reactions[10d] or the
oxidative couplings of 1-benzylisoquinoline.[12] Fꢀrstner and
To identify the optimal reaction conditions for the
reaction, a number of copper catalysts, including CuI, CuCl,
CuBr, Cu2O, and Cu(OAc)2, and several different organic
solvents and ligands were examined in the reaction of 3-
methylindole (1a) with 2-bromophenyl-4-methoxyphenyle-
thyne (2a; Table 1). Interesting observations emerge from the
data in Table 1. We first reacted 1a (0.5 mmol) with 1.1 equiv-
alents of 2a, 10 mol% of CuI, and 1.4 equivalents of KOtBu
in 1.0 mL of DMF at 1108C for 24 hours—the desired
coupling product 3a was not observed (Table 1, entry 1).
However, the addition of 20 mol% of ligand L1 to the
reaction afforded the desired product 3a in a 65% yield
(Table 1, entry 2). The designed ligand L2, was subsequently
found to be more effective than ligand L1 (Table 1, entry 3),
and from entries 4 and 5 in Table 1 it is apparent that the
solvent has a significant influence on the reaction. DMSO was
found to be quite successful for the transformation as
compound 3a was obtained in an 82% yield when DMSO
was used as the solvent instead of DMF (Table 1, entry 4).
When we used toluene as the solvent, the desired product 3a
was obtained in only a 38% yield (Table 1, entry 5). Different
bases were tested in this reaction system, but KOtBu proved
to be most effective (Table 1, entries 4, 6, and 7). The yield of
[*] Dr. A. K. Verma, J. Singh, Dr. V. Tandon
Dr. B. R. Ambedkar Center for Biomedical Research
University of Delhi, Delhi 110007 (India)
E-mail: averma@acbr.du.ac.in
T. Kesharwani, Prof. R. C. Larock
Department of Chemistry, Iowa State University of Science and
Technology, Ames, IA 50011 (USA)
Fax: (+1)515-294-0105
E-mail: larock@iastate.edu
[**] The research work was supported by the Department of Science and
Technology (DST) Government of India and the National Institute of
General Medical Science (GM 070620 and GM 079593). A.K.V. was
awarded a BOYSCAST Fellowship from the DST, Ministry of Science
and Technology, Government of India for the Promotion of Science
for Young Scientists. J.S. is thankful to CSIR. We thank Dr. Ellern
Arkady, Iowa State University, for X-ray crystallographic data.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804427.
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The
2-haloarylalkynes
2a–h required for examining
the scope of this synthesis
were readily prepared by the
standard Sonogashira cou-
pling of the commercially
available 2-bromoiodoben-
zene or 1,2-diiodobenzene
and terminal alkynes. We
avoided the use of 2-iodoar-
ylalkynes because of their
cost and the low yield ini-
tially observed when using
such a substrate. However,
with our optimized reaction
conditions, they appear to
provide results comparable
Scheme 1. The design of direct synthesis of polycyclic heteroaromatic molecules by a tandem reaction.
Table 1: Optimization of the reaction conditions.[a]
to the corresponding bromoarylalkynes (see Table 2, compare
entries 1 and 2). The polycyclic product of the reaction was
fully characterized by H and 13C NMR methods and mass
1
spectroscopic data. The disappearance of the two character-
istic peaks of an alkyne in the 13C NMR spectrum confirmed
the formation of either compound 3a or 6a, but initially it was
difficult to confirm the structure of the regioisomer as either
3a or 6a. X-ray crystallographic analysis of the product
confirmed the presence of 3a, and not 6a.
The scope and limitations of this copper-catalyzed tandem
process were next examined by employing various ortho-
haloarylalkynes and substituted N-heterocycles. The nature of
the heteroarenes and the substituents attached to the triple
bond has a major impact on the success of the process. The
presence of a methoxy group on the arene, para to the triple
bond, increases the electron density on the distal end of the
triple bond, which favors attack at that position and favors a
6-endo-dig cyclization. This effect, in turn, increased the
efficiency of the reaction and the products 3 were obtained in
good yields (Table 2, entries 3, 4, 12, and 15). Alkyne 2 f
having an ortho-methoxy group gave a an inseparable mixture
(Table 2, entry 7), and an alkyne bearing an electron-rich
heterocycle, such as a thiophene, proved favorable for the
reaction (Table 2, entries 8, 9, 13, and 16). The presence of a
methyl group in the 3-position of the indole was found to
increase the efficiency of the transformation, which may be
because of the formation of a more stable transient tertiary
carbocation (Table 2, entries 4–8, and 10). However, the
presence of an electron-withdrawing cyano group in the 3-
position of the indole (Table 2, entry 11) provided an
inseparable mixture of unidentifiable compounds, which
may be the result of the reduced nucleophilicity of the
indole or the formation of a relatively unstable carbocation.
The presence of an electron-donating group in the 5-position
of the indole ring was found to increase the efficiency of the
process, which may be because of an increase in the electron
density at the 2-position of the indole ring, favoring electro-
philic attack onto the alkyne (Table 2, entries 12 and 13),
whereas electron-withdrawing groups gave an unsatisfactory
result (Table 2, entry 14). The reaction of the iodoalkyne 2c
takes place at a lower temperature (1008C) than the
corresponding bromo derivative 2b (1108C), and affords the
Entry Cu cat. (mol%) L (mol%) Base
Solvent t [h] Yield [%][b]
1
2
3
4
5
6
7
8
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuI (2.5)
CuCl (5)
CuBr (5)
Cu2O (5)
Cu(OAc)2 (5)
–
KOtBu DMF
KOtBu DMF
KOtBu DMF
24
0
L1 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
L2 (10)
L2 (5)
L2 (10)
L2 (10)
L2 (10)
L2 (10)
30 65
24 72
KOtBu DMSO 24 82
KOtBu toluene 24 38
NaOtBu DMSO 24 55
Cs2CO3 DMSO 24 47
KOtBu DMSO 24 80
KOtBu DMSO 36 42
KOtBu DMSO 36 39
KOtBu DMSO 36 45
KOtBu DMSO 24 22
KOtBu DMSO 24 48
KOtBu DMSO 24 46
9
10
11
12
13
14
Cu(OAc)2 (10) L2 (20)
[a] All reactions were performed with 1a (0.5 mmol) and 1-bromo-2-(4-
methoxyphenyl)ethynyl)benzene 2a (1.1 equiv), under standard condi-
tions at 1108C under an argon atmosphere. [b] Yield of isolated
products. DMF=N,N-dimethylformamide; DMSO=dimethyl sulfoxide.
the desired product 3a remained almost the same upon
decreasing the CuI catalyst loading from 10 to 5 mol%
(Table 1, entry 8). However, decreasing the catalyst loading
from 5 to 2.5 mol% adversely affected the yield of the
product as compound 3a was obtained in only a 42% yield
(Table 1, entry 9). As in our recent report,[13a] copper(I)
complexes generally give superior results when compared to
copper(II) catalysts in terms of conversion and yield. In fact,
we focused on the use of CuI, since other copper precursors,
such as CuCl, CuBr, Cu2O, and Cu(OAc)2, were found to be
inferior (Table 1, entries 10–14).
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Table 2: Tandem synthesis of diversely substituted indolo- and pyrrolo[2,1-a]isoquinolines catalyzed by
desired cyclized product in a com-
parable yield (Table 2, entry 2).
The trimethylsilyl-substituted
alkyne 2e afforded the desired
cyclization product 3e in a 52%
yield with removal of the trime-
CuI/L2.[a]
Entry
Heterocycle
Alkyne
Product
Yield [%][b]
1
2
3
1b
1b
1b
2b
2c
2a
3b
3b
3c
62
thylsilyl
group,
presumably
because of the basic conditions
employed (Table 2, entry 6). We
extended the scope of the reaction
by employing alkynes having
64[c]
76
amino
substituents
(Table 2,
entries 5, 10, and 17). The reaction
of aminoalkyne 2h with hetero-
cycle 1a, using KOtBu as the base,
gave an inseparable mixture of
products. However, replacing
KOtBu with Cs2CO3 (2.5 equiv)
afforded the desired product 3i in
a 53% yield (Table 2, entry 10). We
have extended the substrate scope
of this reaction by replacing the
indole with a pyrrole, therefore
treatment of 1 f with alkynes 2a,
2g, and 2d afforded the corre-
sponding products 3n, 3o, and 3p
in 78, 72, and 53% yields, respec-
tively (Table 2, entries 15–17).
4
1a
2a
3a
82
5
6
7
1a
1a
1a
2d
2e
2 f
3d
3e
3 f
72
52
The structure of the products 3
[d]
–
was confirmed by the X-ray crys-
tallographic analysis of compounds
3h and 3n (Figure 1). The X-ray
crystallographic results rule out the
formation of product 6 by route A,
and clearly suggest that the prod-
uct 3 must arise through initial
arylation at the C2-position of the
indole and subsequent attack of the
nitrogen nucleophile onto the
8
9
1a
1b
2g
2g
3g
3h
80
72
carbon–carbon
(Scheme 1, route B).
To additionally validate the
formation of products by
route B, we carried out a control
experiment, which involved the
coupling of 4-bromoanisole (7)
with indole 1b and pyrrole 1 f
under identical reaction conditions
(Scheme 2), which afforded the N-
arylated coupling product in excel-
lent yield instead of C2-arylation
products.
After ruling out both of the
routes shown in Scheme 1, we
proposed another possibility for
the formation of the products 3
(Scheme 3). The formation of the
product 3 takes place by initial
attack of the N heterocycle onto
triple
bond
10
11
12
1a
1c
1d
2h
2a
2a
3i
3j
3k
53[e]
3
[d]
–
85
84
13
1d
2g
3l
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Table 2: (Continued)
endo-dig cyclization product; and
2) intramolecular copper-catalyzed
Entry
Heterocycle
Alkyne
Product
Yield [%][b]
À
C C bond formation.
A plausible catalytic cycle for
the above transformation based on
the copper chemistry reported by
[d]
14
1e
2a
3m
–
Knochel and co-workers[4b]
, is
shown in Scheme 5. Presumably,
CuI and ligand L2 generates the
copper complex 13, which upon
oxidative addition and subsequent
complexation with the alkyne
results in the formation of inter-
mediate 14. p Complexation
between the alkyne and the
copper renders haloalkyne com-
plex 14 susceptible to attack by
the heterocyclic nucleophile. Thus,
copper complex 15 is formed by
intermolecular attack of nucleo-
phile 1, which then undergoes
intramolecular attack by C2 of the
N heterocycle and subsequent
15
16
17
1 f
1 f
1 f
2a
2g
2d
3n
3o
3p
78
72
53
[a] All the reactions were carried out using 0.5 mmol of N heterocycle 1 and 1.1 equivalent of 2-
haloarylalkyne 2 in the presence of CuI (5.0 mol%), L2 (10 mol%), and the base (1.4 equiv), in 1 mL
DMSO at 1108C. [b] The yields are based on the product isolated after column chromatography. [c] The
reaction was carried out at 1008C. [d] An inseparable mixture of products was obtained. [e] 2.5 equiv-
alents of Cs2CO3 was used as a base.
Scheme 2. Control experiment confirming N arylation
Figure 1. X-ray crystallographic ORTEP drawings of compounds 3h
and 3n drawn at the 50% probability level.
Scheme 3. A possible pathway.
the carbon–carbon triple bond to generate N-alkenyl inter-
mediate 10, which subsequently cyclizes intramolecularly at
the C2-position of the N heterocycle. Formation of product 3
was confirmed by treating compound 1a with diphenylacety-
lene 11 under similar reaction conditions (Scheme 4). As
expected, spectroscopic identification of the product indi-
cated the formation of the reaction product 12 in an 82%
yield as a mixture of E and Z isomers. This result clearly
supports 1) initial attack of the N nucleophile onto the distal
Scheme 4. Control experiment confirming the attack of the nucleophile
end of the triple bond (activated by copper), which favors a 6- onto the triple bond.
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cycle
1 (0.5 mmol), 2-haloarylal-
kyne 2 (1.1 equiv), and base KOtBt
(1.4 equiv). The Schlenk tube was
capped with a rubber septum and
then evacuated and backfilled with
argon, and DMSO (1 mL) was then
added by syringe through the
septum. The septum was then
replaced with a Teflon screw valve
and the Schlenk tube was sealed.
The reaction mixture was heated to
1108C until 2-haloarylalkyne 2 had
been completely consumed (as
determined by TLC) and was then
cooled to room temperature. The
reaction solution was diluted with
ethyl acetate (10 mL) and water
(15 mL). The layers were separated
and the organic layer was dried over
Na2SO4, and then concentrated
under reduced pressure. The crude
material obtained was then purified
by using flash chromatography on
silica gel (hexanes).
Received: September 8, 2008
Published online: December 29,
2008
Scheme 5. A plausible mechanism.
Keywords: alkynes ·
.
À
benzotriazoles · C C coupling ·
copper · cyclization
elimination of HBr from complex 16, resulting in the
formation of intermediate 17. Reductive elimination of 17
affords product 3 and regenerates copper complex 13. The
other possibility for the formation of 15 involves oxidative
addition of aryl halide 18 to 13. Intermediate 18 could be
obtained by hydroamination of bromoalkyne 2 with indole.
The regioselectivity in the formation of 18 can be explained
by steric effects as observed by Ackermann and Kaspar in
their hydroamination reactions.[17]
In summary, the chemistry described herein provides a
facile and direct synthesis of diversely-substituted, medici-
nally-useful indolo- and pyrrolo[2,1-a]isoquinolines in good
yields with excellent regioselectivity. This chemistry appears
to involve the preferential nucleophilic addition of indoles
and pyrroles onto the ortho-haloarylalkynes over N arylation
of the aryl halide. From a synthetic point of view the net
transformation involves a one-step conversion of simple,
readily available starting materials into an interesting class of
heterocyclic derivatives in good yields. An inexpensive
compound, hydroxymethyl benzotriazole, is used as a ligand
along with inexpensive CuI, thereby increasing the overall
utility of this reaction. This process is expected to find
applications in organic synthesis in general, and in the
construction of a variety of interesting polycyclic hetero-
cycles.
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General procedure: An oven-dried Schlenk tube with a Teflon screw
valve was charged with CuI (5.0 mol%), L2 (10 mol%), N hetero-
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