Generation of indeno[1,2- c ]pyrroles via a pd-catalyzed reaction of 2-alkynylbromobenzene with propargylic sulfonamide

Article abstract of DOI:10.1021/ol300334h

A novel route for the efficient assembly of indeno[1,2-c]pyrrole derivatives via a palladium-catalyzed tandem reaction of 2-alkynylbromobenzene with propargylic sulfonamide is reported. The starting materials are easily available, and the reaction proceed

Full text of DOI:10.1021/ol300334h

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1592–1595
Generation of Indeno[1,2-c]pyrroles via a
Pd-Catalyzed Reaction of
2-Alkynylbromobenzene with
Propargylic Sulfonamide
Yong Luo† and Jie Wu*,†,‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
jie_wu@fudan.edu.cn
Received February 10, 2012
ABSTRACT
A novel route for the efficient assembly of indeno[1,2-c]pyrrole derivatives via a palladium-catalyzed tandem reaction of 2-alkynylbromobenzene
with propargylic sulfonamide is reported. The starting materials are easily available, and the reaction proceeds smoothly with good functional
group tolerance.
According to the CRC dictionary of natural products,
90% of chemically individual molecules discovered in na-
ture contain either a carbocyclic or a heterocyclic subunit.1
Among the methods for access to these skeletons, cycliza-
tion of alkynes provides an efficient and convenient route.2
Recently, intramolecular or intermolecular double insertion
of triple bonds as a key step has been demonstrated as a
powerful strategy for the preparation of heterocyclic or
carbocyclic compounds.3,4 For instance, Lu and co-workers
reported the synthesis of 8H-acenaphtho[1,2-c]pyrroles
via a palladium-catalyzed bicyclization of 1,8-diarenynyl
naphthalenes and primary amines under air in dimethyl
sulfoxide.3b We also found that various heterocycles
containing an indene skeleton could be synthesized
through a palladium-catalyzed double insertion of a
triple bond with amine, phenol, or amide.4 During the
process, several side reactions are minimized since the
insertion of the triple bond was preferred, compared
with the direct CꢀN or CꢀO coupling. With these pro-
mising results in hand, we further consider expanding
the utility of this strategy, with an expectation to intro-
duce more scaffold diversity for different biological
evaluations.
† Fudan University.
‡ Chinese Academy of Sciences.
(1) Dictionary of Natural Products, version 14.1; Chapman & Hall/CRC
Informa: London, 2005.
€
(2) Recent reviews: (a) Kruger, K.; Tillack, A.; Beller, M. Adv. Synth.
Catal. 2008, 350, 2153. (b) Balme, G.; Bossharth, E.; Monteiro, N. Eur.
J. Org. Chem. 2003, 4101. (c) Guo, L.-N.; Duan, X.-H.; Liang, Y.-M.
Acc. Chem. Res. 2011, 44, 111. (d) Sohel, S.;Md., A.;Liu,R.-S. Chem. Soc.
Rev. 2009, 38, 2269. (e) Yamamoto, Y.; Gridnev, I. D.; Patild, N. T.; Jin, T.
Chem. Commun. 2009, 5075. (f) Cacchi, S.; Fabrizi, G.; Goggiamani,
A. Org. Biomol. Chem. 2011, 9, 641. (g) Gilmore, K.; Alabugin, I. V. Chem.
Rev. 2011, 111, 6513. (h) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004,
104, 2127.
(3) (a) Chen, X.; Lu, P.; Wang, Y. Chem.;Eur. J. 2011, 17, 8105. (b)
Chen, X.; Jin, J.; Wang, Y.; Lu, P. Chem.;Eur. J. 2011, 17, 9920.
(4) (a) Luo, Y.; Hong, L.; Wu, J. Chem. Commun. 2011, 47, 5298. (b)
Luo, Y.; Pan, X.; Wu, J. Org. Lett. 2011, 13, 1150. (c) Pan, X.; Luo, Y.;
Wu, J. Chem. Commun. 2011, 47, 8967. (d) Luo, Y.; Wu, J. Chem.
Commun. 2011, 47, 11137. (e) Pan, X.; Luo, Y.; Liu, G.; Pu, S.; Wu, J.
Adv. Synth. Catal. 2012, 354, 171.
Indeno[1,2-c]pyrrole with a 6-5-5 scaffold containing a
pyrrole core has drawn our attention since remarkable bio-
logical activities of these compounds have been reported.5
(5) (a) Huck, B. R.; Llamas, L.; Robarge, M. J.; Dent, T. C.; Song, J.;
Hodnick, W. F.; Crumrine, C.; Stricker-Krongrad, A.; Harrington, J.;
Brunden, K. R.; Bennani, Y. L. Bioorg. Med. Chem. Lett. 2006, 16, 4130.
(b) Qiao, L.; Zhao, L.-Y.; Rong, S.-B.; Wu, X.-W.; Wang, S.; Fujii, T.;
Kazanietz, M. G.; Rauser, L.; Savage, J.; Roth, B. L.; Flippen-Anderson,
J.; Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2001, 11, 955. (c) Behler, F.;
€
Habecker, F.; Saak, W.; Kluner, T.; Christoffers, J. Eur. J. Org. Chem.
2011, 4231. (d) Zhou, W.; An, G.; Zhang, G.; Han, J.; Pan, Y. Org. Biomol.
Chem. 2011, 9, 5833.
r
10.1021/ol300334h
Published on Web 03/05/2012
2012 American Chemical Society

Prompted by the recent results for the generation of cyclic
compounds using the strategy3,4 of palladium-catalyzed
double insertion of a triple bond, we envisioned that indeno-
[1,2-c]pyrrole derivatives could be constructed through a
palladium-catalyzed reaction of 2-alkynylbromobenzene
with propargylic sulfonamide. The proposed synthetic route
isillustratedinScheme1. Wehypothesizedthatanoxidative
addition of Pd(0) to 2-alkynylbromobenzene 1 would occur
first to generate a Pd(II) species A. Coordination and
insertion to the triple bond of propargylic sulfonamide 2
would result in the formation of intermediate B. Then an
intramolecular insertion of a triple bond would take place to
produce intermediate C, which would subsequently undergo
a CꢀN coupling to afford the desired indeno[1,2-c]pyrrole 3.
During the reaction process, three bonds would be
Our initial attempt was performed for the reaction of
1-bromo-2-(phenylethynyl)benzene 1a with 4-methyl-N-
(3-(p-tolyl)prop-2-yn-1-yl)benzenesulfonamide 2a in the
presence of Pd(OAc)2 (5 mol %) and K2CO3 in 1,4-
dioxane under reflux (Table 1). At first, various phosphine
ligands were examined (Table 1, entries 1ꢀ5). However,
only a trace amount of product was detected when DPPP,
DPPF, PCy3, or XantPhos (L1) was used in the reaction.
To our surprise, compound 4a was isolated in 39% yield as
an isomer11 of the desired indeno[1,2-c]pyrrole 3a when
DPEPhos (L2) was employed as a ligand (Table 1, entry 5).
A comparable result was obtained when the reaction
was performed in toluene (Table 1, entry 6). The result
was inferior when DMF or DMSO was employed as
the solvent (Table 1, entries 7 and 8). A slightly higher
yield was generated when the amount of sulfonamide
2a and Pd(OAc)2 was increased (Table 1, entries 9 and 10).
Interestingly, we found that the presence of a weaker
base combined with a lower temperature led to the
desired product 3a (Table 1, entries 11ꢀ14). The structural
Scheme 1. Proposed Synthetic Route to Indeno[1,2-c]pyrroles
via a Palladium-Catalyzed Reaction of 2-Alkynylbromoben-
zene with Propargylic Sulfonamides
Table 1. Initial Studies for the Palladium-Catalyzed Reaction of
1-Bromo-2-(phenylethynyl)benzene 1a with 4-Methyl-N-(3-(p-
tolyl)prop-2-yn-1-yl)benzenesulfonamide 2aa
entry
[Pd]
ligand
base
solvent yield (%)b
1
2
3
4
5
6
7
8
9c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DPPP K2CO3
DPPF K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
trace
trace
PCy3
L1
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
trace
trace
4a (39)
4a (40)
trace
DMSO
toluene
toluene
trace
4a (43)
4a (46)
3a (32)
trace
formed in a tandem sequence. Although it seems feasible
theoretically, there are still some challenges that usually
appear in the formation of pyrroles using propargylic amides
as starting materials:6ꢀ8 (a) the direct CꢀN coupling seems
inevitable under the palladium-catalyzed conditions;9 (b) a
β-elimination with the formation of allene often occurs.10
Encouraged by our recent results,4 we conceived that all of
these side reactions and byproducts might be minimized
under suitable conditions. Herein, we disclose our recent
efforts for the synthesis of indeno[1,2-c]pyrrole derivatives
via a palladium-catalyzed tandem reaction of 2-alkynylbro-
mobenzene with propargylic sulfonamide.
10c,d Pd(OAc)2
11c,d
12
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Na2CO3 toluene
Cs2CO3 toluene
iPr2NEt toluene
13
trace
14c,d Pd(OAc)2
15c,d Pd(PPh3)4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
3a (42)e
3a (30)e
trace
16e
Pd2(dba)3
17c,d Pd(PhCN)2Cl2 L2
18e
[Pd(allyl)Cl]2 L2
3a (55)e
trace
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), palladium
catalyst (5 mol %), ligand (10 mol %), base (0.4 mmol), solvent (2.0 mL).
b Isolated yield based on 1-bromo-2-(phenylethynyl)benzene 1a. c 2a (0.3
mmol) was used. d In the presence of [Pd] (10 mol %). e The reaction
occurred at 80 °C. XantPhos (L1): 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene. DPEPhos (L2): 2-(dicyclohexylphosphino)-20,40,60-
tri-isopropyl-1,10-biphenyl.
(6) Yamagishi, M.; Nishigai, K.; Hata, T.; Urabe, H. Org. Lett. 2011,
13, 4873.
(7) (a) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343. (b)
Zhang, Q.; Xu, W.; Lu, X. J. Org. Chem. 2005, 70, 1505.
(8) Ma, S.; Wu, B.; Jiang, X. J. Org. Chem. 2005, 70, 2588.
(9) Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122,
10220.
(10) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M.
J. Organomet. Chem. 2003, 687, 562.
(11) The isomerization could easily happen under basic condition at
high temperature: (a) Samet, A. V.; Yamskov, A. N.; Strelenko, Y. A.;
Semenov, V. V. Tetrahedron 2009, 65, 6868. (b) Noland, W. E.; Lanzatella,
N. P. J. Heterocycl. Chem. 2009, 46, 1285. (c) Kim, H. S.; Lee, H. S.; Kim,
S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 3154.
Org. Lett., Vol. 14, No. 6, 2012
1593

Scheme 2. Reactions of 1-Bromo-2-(phenylethynyl)benzene 1a
with Several R-Substituted Propargylic Sulfonamides
Scheme 3. Palladium-Catalyzed Tandem Reaction of 2-Alky-
nylbromobenzene 1 with Propargylic Sulfonamide 2a
a 0.5 mL of solvent was used.
b 0.5 mL of solvent and 0.24 mmol of 2e were used.
elucidation was demonstrated by X-ray diffraction
analysis (see the Supporting Information). The reac-
tions were complex when strong bases were employed.
Further screening of palladium catalysts revealed that
Pd(PhCN)2Cl2 was the best choice compared with Pd-
(OAc)2, Pd(PPh3)4, Pd2(dba)3, and [Pd(allyl)Cl]2 (Table 1,
entries 15ꢀ18).
We noticed that, during the reaction process, all of the
starting materials were consumed and we did not observe
other major byproducts. Since excess sulfonamide was
utilized in the reaction, we assumed that the R-unsubsti-
tuted propargylic sulfonamide 2a might generate unstable
intermediates, which thus could not complete the reaction
cycle. Therefore, several R-substituted propargylic sulfon-
amides were synthesized and applied to the reaction of
1-bromo-2-(phenylethynyl)benzene 1a under the opti-
mized conditions highlighted in Table 1 (Scheme 2). From
the results, it suggested that the substitutions at the
R-carbon of propargylic sulfonamides could have great
impact for the outcome. When R-dimethyl-substituted
propargylic sulfonamide was employed as a substrate,
the reaction provided the corresponding product in
72% yield under the standard condition. After further
screening, we found that the effect of starting materials’
concentration could not be ignored. When 0.5 mL of
solvent was used in this reaction, indeno[1,2-c]pyrrole
3e could be generated in 82% yield.
a Isolated yield based on 2-alkynylbromobenzene 1.
b 2.0 mL of toluene was used.
no direct coupling or β-elimination products were ob-
served. Removal of acetyl group of compound 3j was
tried under different conditions according to literature
reports. However, we did not obtain the expected free amine
compound. Instead, compound 5 was generated. The best
yield (62%) was obtained when the reaction occurred in the
presence of KOH (Scheme 4). This phenomenon was also
observed in our previous work.4c
Scheme 4. Removal of Acetyl Group of Compound 3j
With these results in hand, we next investigated
the scope and generality of this palladium-catalyzed
tandem reaction of 2-alkynylbromobenzene with pro-
pargylic sulfonamide (Scheme 3). Not only sulfon-
amides but also amides were all suitable reactants
during the transformation. However, the reaction was
complex when amine was used. The substituents on the
2-alkynylbromobenzene 1 or propargylic sulfonamide
2 (no matter whether electron-donating or electron-
withdrawing) did not obviously affect the formation of
the desired products 3. Additionally, this reaction
showed good functional group tolerance because car-
bonyl (ester and ketone) and nitro groups survived in
the conversion. It is also noteworthy that, in all cases,
In conclusion, we have described a novel route for
the efficient assembly of indeno[1,2-c]pyrrole deriva-
tives via a palladium-catalyzed tandem reaction of
2-alkynylbromobenzene with propargylic sulfona-
mide. This strategy involving double insertion of triple
bonds shows high efficiency with good functional
1594
Org. Lett., Vol. 14, No. 6, 2012

group tolerance. Currently, using this strategy for the
construction of other privileged scaffolds is under in-
vestigation in our laboratory.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3, and a CIF file of compound 3a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from National Nat-
ural Science Foundation of China (Nos. 21032007 and 2117-
2038) is gratefully acknowledged.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1595