Base-Controlled Cu-Catalyzed Tandem Cyclization/Alkynylation for the Synthesis of Indolizines

Article abstract of DOI:10.1021/acs.orglett.6b00821

A base-controlled Cu-catalyzed tandem cyclization/alkynylation of propargylic amines provides rapid access to functionalized indolizine derivatives under mild reaction conditions. The reaction first proceeded via a 5-endo-dig aminocupration, followed by a coupling between the copper-bound intermediate and alkynyl bromide, to afford the products in good to excellent yields. The successful tandem reaction is attributed to the unique property of the bases, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene used).

Full text of DOI:10.1021/acs.orglett.6b00821

Letter
pubs.acs.org/OrgLett
Base-Controlled Cu-Catalyzed Tandem Cyclization/Alkynylation for
the Synthesis of Indolizines
Kyung Hwan Oh, Seong Min Kim, Sun Young Park, and Jin Kyoon Park*
Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 609-735, Korea
S
* Supporting Information
ABSTRACT: A base-controlled Cu-catalyzed tandem cycliza-
tion/alkynylation of propargylic amines provides rapid access
to functionalized indolizine derivatives under mild reaction
conditions. The reaction first proceeded via a 5-endo-dig
aminocupration, followed by a coupling between the copper-
bound intermediate and alkynyl bromide, to afford the
products in good to excellent yields. The successful tandem
reaction is attributed to the unique property of the bases, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and MTBD (7-methyl-
1,5,7-triazabicyclo[4.4.0]dec-5-ene used).
Scheme 1. Working Hypothesis of a Base-Controlled
Copper-Catalyzed Annulative Direct Alkynylation
he synthesis of fused N-heterocycles has attracted a great
Tdeal of attention owing to its broad application in
medicinal1 and material chemistry.2 In particular, N-hetero-
cycles are utilized in the development of potent bioactive
compounds3 and highly efficient electronic materials.4 Over the
past decade, transition-metal-catalyzed aminometalation5 of
alkynes has been widely used for the synthesis of heterocycles
such as indolizines.6 A tandem reaction strategy has been used
to access diversely functionalized indolizines as well, utilizing a
metal-bound intermediate generated in situ for the subsequent
C−C coupling reaction with prechosen reagents.7 The
procedure benefits from good atom and step economy, offers
flexibility in constructing the organic backbone, and has
excellent selectivity in the C−C bond forming reaction. To
date, most examples are limited to Pd catalysis for the synthesis
of indolizine involving cycloisomerization, followed by C−C
coupling reactions such as addition reaction,7a arylation,7b,c
carbonylative carbonylation,7d and oxidative arylation.7 These
e
methods, however, require harsh reaction conditions and
expensive metal and ligand. Interestingly, the copper-catalyzed
tandem C−C coupling reaction has rarely been explored
despite copper metal’s natural abundance and cheap price.8
With regard to the C−C bond formation for tandem
reaction, we initially focused on the metal-catalyzed C−H
direct alkynylation of heterocycles using bromoalkyne.9 There
are limited examples of copper-catalyzed reactions, typically
involving a direct deprotonation by a strong base to generate a
heterocycle-bound σ-copper(I) intermediate (Scheme 1-1).9d,e
We surmised that if the copper(I) intermediate is produced via
mild cycloisomerization6f,10 instead of a harsh, direct
deprotonation process as described above, it can be
subsequently utilized for alkynylations. Recently, the simple
cyclizations of propargylic pyridine with Et3N or without base,
in the presence of Cu(I), to indolizines were reported by Liu6f
and Gevorgyan.6h Liu proposed that the cyclization reaction
was accomplished by a sequential process of aminocupration,
followed by protonolysis of the copper(I) intermediate, 1.
(Scheme 1-2).
Based on the two examples (Scheme 1-1 and 1-2), we
hypothesized that if the base is strong enough to trap the acid
generated during the intramolecular nucleophilic attack of
pyridine to the copper-activated π-bond and could stabilize the
copper(I) as a ligand, the copper(I) intermediate, 1, would
survive the protonolysis step and react with a bromoalkyne
species to give an alkynylated indolizine (Scheme 1-3).
Stepwise synthesis of an alkynylated indolizine has been
reported by the Kim group.6m Herein, we describe a mild
base-controlled Cu-catalyzed in situ oxidative alkynylation
reaction, which occurs after an intramolecular aminocupration
of N-heterocycles to copper-bound alkyne, to give indolizine
derivatives using bicyclic bases.
Received: March 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00821
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Organic Letters
Letter
To test our hypothesis, we experimented using the known
cycloisomerization conditions,6f which employed Et3N in
CH3CN (Table 1, entry 1). Unsurprisingly, we observed only
DBN led to a significant drop in yield (18%) (entries 8−9).
Finally, the screening of alcoholic solvents revealed that n-
BuOH was better than EtOH, MeOH, n-PrOH, and i-PrOH,
giving a 97% yield of 3a and an undetectable amount of the
simple cyclization product, 3a′, in n-PrOH, i-PrOH, and n-
BuOH (entries 10−14). Despite a slightly lower yield, i-PrOH
was chosen as the reaction solvent because n-BuOH has a
higher boiling point and an unpleasant odor. The optimum
base in i-PrOH was also MTBD, giving a 94% yield of 3a (entry
15). In order to investigate the effect of solvent on the
formation of 3a, the reaction was performed in i-PrOH with
Et3N but minimal alkynylation was observed (entry 1 vs 16).
To evaluate the synthetic scope of this method, we tested
different types of bromoalkynes to ascertain whether the
reaction conditions can accommodate a wide range of
functionalities (condition A). gem-Dibromo alkenes were also
tested as an equivalent of bromoalkyne, and the reaction
conditions were further optimized in one pot (condition B).
Most product yields obtained with gem-dibromo alkenes were
slightly lower than those with 1-bromoalkynes, presumably
owing to a loss in yield during the first elimination step
(Scheme 2). Aromatic rings bearing ortho-, meta-, and para-
electron-withdrawing, as well as electron-donating, substituents
were well tolerated to give the desired products (3a−n) in 76−
91% yields except for the nitro substituent, which gave 3o−p in
32−64% yields. In addition, 1- and 2-naphthyl substrates gave
the desired compounds, 3q−r in 69−88% yields, whereas
heterocyclic substrates gave 3s−t in 69−90% yields. In order to
expand the scope of the pyridine moiety, we attempted to
prepare the product, 3u−y. Using fused pyridine substrates,
pyrrolo[1,2-a]quinolone, 3u, and pyrrolo[2,1-a]isoquinoline,
3v, were successfully prepared in good yields (74−81%). The
methyl group at C-6 of pyridine did not decrease the yield of
3w (90%). Electron-withdrawing bromine at C-5 gave a 52%
yield of 3x, and fluorine at C-3 had almost no influence on the
yield of 3y (91%). When we attempted to synthesize the hexyl
ethynyl product 3z, it was found that bromooctyne reacted
readily to give an 85% yield but the reaction was unsuccessful
with gem-dibromooctene.12 This could be caused by an
absence of an elimination reaction of the gem-dibromooctene
under the reaction conditions. TBDMS ether and phenyl ether
were also tolerated to afford the desired products, 3aa and 3ab,
in 60% and 81% yields. It is valuable to note that most
substrates gave almost no detectable simple cyclization
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 2 (1.0 equiv), bromoalkyne (1.5 equiv), CuCl
b
(20 mol %), base (1.2 equiv), solvent (0.3 M), rt, 20 min. pKa of the
conjugate acid of amine in acetonitrile:11 Et3N (18.82), 2,6-lutidine
(14.13), proton sponge (18.62), Hunig base (−), DABCO (−), TBD
̈
c
(25.98), MTBD (25.44), DBN (23.89), DBU (24.33). NMR yield
d
based upon internal standard (dibromomethane). CuBr and CuI gave
the same results.
1
products with bromoalkynes and dibromoalkenes in crude H
NMR.
6% of the desired product, 3a, based on the crude NMR
analysis. Next, we tested other bases while maintaining the use
of CH3CN, and the yields of the desired product increased
accordingly: from 10% to 58% with bases such as 2,6-lutidine,
DABCO (1,4-diazabicyclo[2.2.2]octane), proton sponge (1,8-
The alkyne moiety in propargylic pyridines bearing the alkyl
and alkenyl groups, 4a and 4b, reacted well with 1-bromo-2-
phenylacetylene (Scheme 3). In the case of hexyl propargylic
pyridine, 4a, MTBD was an optimal base to afford 82% of the
product in 2 h. Meanwhile, vinyl propargylic pyridine, 4b, gave
an 83% yield under the standard reaction conditions.
Unfortunately, the alkynyl-substituted propargylic pyridine,
4c, was not successful in affording the desired product, 5c.
Recently, fluorescent indolizines13 have been applied for the
use of biological imaging. The Park group13a and You and Lan
group13b have developed full-color-tuned fluorescent probes for
cell assay, independently. In order to show functional group
compatibility, easy access to coupling with complex molecules,
and potent bioapplications of indolizine as imaging units, we
attempted to a combination with bioactive steroids, such as
ethisterone and ethynylestradiol, and the reaction proceeded
bis(dimethylamino)naphthalene), and Hunig base (N,N-
̈
diisopropylethylamine) (entries 2−5). We then proceeded to
test bicyclic amine bases (Table 1, entries 6−9), which include
TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), MTBD (7-methyl-
1,5,7-triazabicyclo[4.4.0]dec-5-ene), DBN (1,5-diazabicyclo-
[4.3.0]non-5-ene), and DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene). TBD, a secondary amine, was incompatible as most of 2a
disappeared during the reaction, giving a minimal amount of
the product (entry 6). Surprisingly, only the desired product
was formed (at a moderate yield) when MTBD was used,
showing the absence of the cyclized product, 3a′ (entry 7).
DBU gave the highest yield (78%) in CH3CN while employing
B
DOI: 10.1021/acs.orglett.6b00821
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Organic Letters
Letter
Scheme 2. Synthesis of Indolizines from 2 with 1-
Bromoalkynes or gem-Dibromoalkenes
Scheme 3. Synthesis of Indolizines from Alkyl, Alkenyl, and
Alkynyl Propargylic Pyridines
ab
,
a
b
MTBD was used for 2 h. DBU was used for 20 min.
Figure 1. Synthesis of indolizine, 6 and 7 from bromo ethylestradiol
acetate and bromo ethisterone.
For a mechanistic explanation, there are two possible
reaction pathways (Scheme 4). In path 1, Cu(I) is first
Scheme 4. Proposed Mechanism
coordinated by the alkyne, followed by a nucleophilic attack of
the alkyne by the pyridine nitrogen via a 5-endo-dig cyclization,
as reported in the literature.6d−f Next, DBU (or MTBD)
deprotonates the cyclized zwitterionic salt, 9. As for path 2, the
same cyclized zwitterionic salt, 9′, could be produced via a
propargyl-allenyl isomerization, followed by an intramolecular
amine attack of the Cu-bound allenyl double bond. It is
presumed that the basicity of DBU (or MTBD) is strong
enough to prevent the copper intermediate, 1, from undergoing
protonolysis;11 thus, 1 readily associates with the bromoalkyne
to generate 10, which then undergoes reductive elimination to
form the desired product, 3. At the same time, bulky DBU (or
MTBD) may serve as a good ligand to inhibit the copper
intermediate from protonolysis and to facilitate the oxidative
a
Isolated yield under condition A [2 (1.0 equiv), bromoalkyne (1.5
equiv), CuCl (20 mol %), DBU (1.2 equiv), i-PrOH (0.3 M), rt, 20
b
min]. Isolated yield was shown in the parentheses under condition B
[2 (1.0 equiv), dibromoalkene (1.5 equiv), DBU (3.0 equiv), DMSO
(0.6 M), rt, 30 min; CuCl (20 mol %), n-BuOH (0.2 M), rt, 20 min].
c
MTBD was used at 30 °C for 2 h.
smoothly to afford 6 and 7 in 72% and 75% yields under the
standard conditions (Figure 1).
C
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(4) Wan, J.; Zheng, C.-J.; Fung, M.-K.; Liu, X.-K.; Lee, C.-S.; Zhang,
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alkynylation reaction. Investigation of the kinetic isotope effect
using [D]-2 revealed that the rate-determining step involves
cleavage of the C−H bond (kH/kD = 4.48)14 which may occur
in propargyl-allenyl isomerization15 and/or deprotonation of
the zwitterionic salt.16 An unsuccessful C−H direct alkynylation
under the standard reaction conditions used supports our
proposed mechanism (Scheme 5).
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Scheme 5. Unsuccessful Attempt of C−H Direct
Alkynylation
In summary, we have developed a base-controlled Cu(I)-
catalyzed tandem cyclization/alkynylation of propargylic
pyridines which provides rapid and functional group tolerant
access to indolizines. Halide-substituted propargylic pyridines
and bromoalkynes are also compatible with the reaction
conditions, which might be challenging substrates if used in
the case of a Sonogashira reaction. The reaction proceeds via a
5-endo-dig aminocupration of propargylic ester, followed by a
copper-catalyzed coupling reaction with alkynyl bromide or
alkenyl dibromide. This method was also successfully applied to
the synthesis of steroid-substituted indolizines. This work
demonstrates that the tandem C−C coupling reaction could be
realized with an inexpensive copper catalyst with the proper
choice of bases.
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Gevorgyan, V. Org. Lett. 2012, 14, 6056.
(8) For stoichiometric reactions for indole synthesis, see: Hirano, K.;
Miura, M. Chem. Commun. 2012, 48, 10704.
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haloalkyne other than copper, see: (a) Seregin, I. V.; Ryabova, V.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (b) Matsuyama, N.;
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For a review paper, see: (d) Dudnik, A. S.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2010, 49, 2096. For Cu-catalyzed direct alkynations,
see: (e) Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48,
̀
9553. (f) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M.
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1138.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00821.
Experimental procedures, full characterization of prod-
ucts, and NMR spectra (PDF)
(11) Kaljurand, I.; Kutt, A.; Soovali, L.; Rodima, T.; Maemets, V.;
Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
̈
̈
̈
AUTHOR INFORMATION
■
Corresponding Author
(12) Morri, A. K.; Thummala, Y.; Doddi, V. R. Org. Lett. 2015, 17,
4640.
*E-mail: pjkyoon@pusan.ac.kr.
Notes
(13) (a) Kim, E.; Lee, Y.; Lee, S.; Park, S. B. Acc. Chem. Res. 2015, 48,
538. (b) Liu, B.; Wang, Z.; Wu, N.; Li, M.; You, J.; Lan, J. Chem. - Eur.
J. 2012, 18, 1599.
(14) More details are given in the Supporting Information.
(15) Dabrowski, J. A.; Haeffner, F.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2013, 52, 7694.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was financially supported by the National Research
Foundation of Korea (NRF) funded by the Korean Govern-
ment (2013R1A1A1011793) and the Nano Material Develop-
ment Program (2012M3A7B4049644) through the National
Research Foundation of Korea (NRF) funded by the Ministry
of Education, Science and Technology (MEST). Finally, J.K.P.
thanks the Posco TJ Park Foundation for their generous
support.
(16) Maresh, J. J.; Giddings, L.-A.; Friedrich, A.; Loris, E. A.; Panjikar,
S.; Trout, B. L.; Stockigt, J.; Peters, B.; O’Connor, S. E. J. Am. Chem.
̈
Soc. 2008, 130, 710.
REFERENCES
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DOI: 10.1021/acs.orglett.6b00821
Org. Lett. XXXX, XXX, XXX−XXX