Copper catalyzed synthesis of highly substituted pyrrole and isoindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.09.070

We have developed an efficient synthesis of highly substituted pyrrole and isoindole derivatives using copper(I) catalyst. This methodology is helpful for the synthesis of some quinones bearing annealed N-heterocyclic natural products.

Full text of DOI:10.1016/j.tetlet.2011.09.070

Tetrahedron Letters 52 (2011) 6203–6206
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Copper catalyzed synthesis of highly substituted pyrrole
and isoindole derivatives
⇑
Sukla Nandi, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient synthesis of highly substituted pyrrole and isoindole derivatives using
copper(I) catalyst. This methodology is helpful for the synthesis of some quinones bearing annealed N-
heterocyclic natural products.
Received 2 August 2011
Revised 13 September 2011
Accepted 15 September 2011
Available online 21 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
Phenylhydroxylamine
N-Containing heterocycles
Pyrrole
Isoindole
The pyrrole and isoindole moieties have become attractive tar-
gets in organic and medicinal chemistry. Among numerous hetero-
cycles, the pyrrole moiety has always been one of the most
prominent since it is found in natural products1 and electrically
conducting materials such as polypyrroles.2 In particular, substi-
tuted pyrroles are highly biologically active and have proven to
display antibacterial,3 antiviral (also anti-HIV-1),4 antiinflamma-
tory,5 and antioxidant6 activities as well as inhibitor of cytokine-
mediated diseases.7 On the other hand, isoindoles can also be
potential precursors of porphyrin analogs or pyrroles with ex-
tended conjugation and therefore, should find important applica-
tions in materials science.8 Moreover, isoindoles have been
widely used for their high level of reactivity in cycloaddition reac-
tions9 and, more recently, isoindoles and their derivatives have be-
come attractive candidates for organic light-emitting devices
(OLEDs) due to their high fluorescent and electroluminescent prop-
erties.10 However, they are rather unstable and their preparatory
methods are still limited, especially in a catalytic fashion, which
creates a demand for new and straightforward methodologies to
access these substrates. These heterocyclic frameworks are an inte-
gral part of the structure of some biologically active compounds as
well as that of natural products such as Reniera indole, which have
been isolated from the blue sponge Reniera sp.11 azamonosporas-
cone. This fungus (azamonosporascone) has been found to be
OH
O
O
OH
O
O
COOH
O
Me
N
Me
N
MeO
OH
MeO
NH
N
Me
Me
OH
OH
O
O
O
O
Reniera indole
Azamonosporascone
Bhimamycin C
Bhimamycin D
Figure 1. Some biologically active natural products.
⇑
Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.070

6204
S. Nandi, J. K. Ray / Tetrahedron Letters 52 (2011) 6203–6206
responsible for crop losses of musk melon and watermelon,12 bhi-
mamycin C, and bhimamycin D (Fig. 1) which display bioactivities
against human ovarian cancer cell lines and are also EP4 receptor
agonists in the treatment of pain.13
Ph
O
Ph
ArNHOH, Et3N, Cu(I)
DMF, H2O, 90 o
N
Ar
C
CHO
As a consequence, many synthetic methods are known from
early days for the construction of the pyrrole and isoindole moi-
eties. The most frequently used methods include the classical
cyclocondensation of primary amines with 1,4-dicarbonyl com-
2
1
Scheme 1. Synthesis of substituted pyrrole and isoindole rings by copper-catalyzed
reaction.
pounds (Paal–Knorr synthesis), the reaction between an
ketone and a b-ketoester or b-diketone (Knorr pyrrole synthesis),
the condensation between an -halo ketone, a b-ketoester, and a
a-amino
a
primary amine or ammonia (Hantzsch procedure), and various
cycloaddition strategies. However, these methods have some lim-
itations with respect to the desired regioselectivity and substitu-
tion patterns. Many methods for the synthesis of pyrrole14 and
isoindole15 have been developed recently, including the one-pot
methodology developed by our group.16 In spite of recent ad-
vances, particularly in transition metal mediated multi-compo-
nent reactions, a more flexible and generalized methodology
Ph
Br
O
Ph
H
PBr3, DMF
CHCl3
CHO
CHO
1a-1h
CuI, Pd(PPh3)2Cl2
Et3N
Scheme 2. Synthesis of starting materials.
Table 1
Optimization studiesa
Ph
O
Ph
Ph
H
Ph
PhNHOH
N
Ph
CHO
1a
2a
Entry
Catalyst (10 mol %)
Base (1 equiv)
Solvent
Temp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuBr
CuI
CuCl
CuCl
CuBr
CuCl
CuCl
Et3N
Et3N
Et3N
Et3N
K2CO3
Et3N
Et3N
Na2CO3
K2CO3
DMF
DMF
DMF
DMF
CH3CN
CH3CN
Toluene
Toluene
DMF
85–90
65–70
85–90
85–90
85
85
95
95
85–90
78
46
20
10
0
10
0
0
0
a
All the reactions were carried out in the presence of 5 equiv H2O, under argon atm.
Table 2
Copper-catalyzed synthesis of pyrroles and isoindolesa
Entry
Substrates
Products
Yield (%)
82
Ph
O
Ph
Ph
Ph
Ph
PhNHOH
1
N
CHO
1a
2a
Ph
O
Ph
Ph
Ph
HOHN
CH3
2
3
78
77
N
CH3
CHO
1b
2b
O
Ph
PhNHOH
Ph
H3C
H3C
N
Ph
1c
2c
CHO
(continued on next page)

S. Nandi, J. K. Ray / Tetrahedron Letters 52 (2011) 6203–6206
6205
Table 2 (continued)
Entry
Substrates
Products
Yield (%)
O
Ph
HOHN
Ph
4
5
H3C
69
81
H3C
CH3
N
CH3
1d
2d
Ph
CHO
Ph
Ph
O
O
PhNHOH
HOHN
N
Ph
CHO
CHO
CHO
CHO
1e
2e
Ph
CH3
6
7
78
72
67
N
CH3
1f
1g
1h
2f
2g
2h
Ph
O
O
Ph
PhNHOH
N
Ph
Ph
HOHN
Ph
CH3
8
N
CH3
a
Reagents and conditions: 1a–1h (1 equiv), ArNHOH (1.2 equiv), CuCl (10 mol %), Et3N (1 equiv), H2O (5 equiv), DMF (5 mL), 85–90 °C.
that is tolerant of a large number of functional groups is still
needed. Considering their potential biological relevance herein
we report a synthetic approach to highly substituted pyrroles
and isoindoles using 1 (Scheme 1).
The convergent approach involved the preparation of precur-
sors 1a–1h, which were efficiently synthesized from bromovinylal-
dehydes by Sonogashira coupling17 as per Scheme 2.
The initial experiment was carried out by heating a mixture of
compound 1a (1 equiv), phenylhydroxylamine (1.2 equiv), H2O
(5 equiv), Et3N (1 equiv), and CuCl (cat.) in DMF at 85–90 °C under
argon atmosphere for 2 h (Table 1, entry 1). A pyrrole ring resulted
from the substrate 1a, but when the reaction was carried out in an
open flask or in the absence of water the product yield was very
low along with other side products. By lowering the temperature
to 60 °C, very low yields were obtained (Table 1, entries 2 and 3).
The reaction was then attempted by changing the catalyst, base,
and solvent to optimize the reaction conditions. The results are
summarized in Table 1. Finally, we concluded that our optimized
condition was CuCl (10 mol %), 5 equiv H2O, 1 equiv Et3N in 4–
5 mL DMF, heated at 85–90 °C for 2 h. We next examined the scope
of this reaction with different 3-(1-alkynyl)-2-alkene-1-als (1a–
1h) with ArNHOH to obtain the pyrrole or isoindole ring in com-
pounds 2a–2h in moderate to good yield18 which are shown in Ta-
ble 2. The crystal structure of isoindole 2f19 is shown in Scheme 3
which confirms the product structure.
In view of the absence of any supporting evidence, at this point,
we are unable to produce any mechanistic explanation other than
the account of the formation of the observed products.
When we used 3-(4-methoxyphenyl)-5-phenylpent-2-en-4-
ynal as a starting material we did not get any pyrrole product
MeO
Ph
O
O
PhNHOH (1.2 equiv)
Et3N (1 equiv)
H
H
H
H
No reaction
CuCl (10 mol%)
H2O (5 equiv), DMF, 90 oC
MeO
Ph
Scheme 3. Crystal structure of isoindole 2f with 50% probability.
Scheme 4. Reaction with 3-(4-methoxyphenyl)-5-phenylpent-2-en-4-ynal.

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S. Nandi, J. K. Ray / Tetrahedron Letters 52 (2011) 6203–6206
T. D.; Chandrasekar, P.; Osuma, A. T.; Chaney, S. T.; Spence, J. D. J. Org. Chem.
1998, 63, 8455; (d) Lash, T. D.; Werner, T. M.; Thompson, M. L.; Manley, J. M. J.
Org. Chem. 2001, 66, 3152; (e) Duan, S.; Sinha-Mahapatra, D. K.; Herndon, J. W.
Org. Lett. 2008, 10, 1541; (f) Paolesse, R. Synlett 2008, 2215.
(Scheme 4). This may be due to the conjugation of the lone electron
pair of the oxygen with the aldehyde group.
In conclusion, we have developed a new methodology for the
synthesis of highly substituted pyrrole and isoindole rings by reac-
tion of substituted 3-(1-alkynyl)-2-alkene-1-als with arylhydr-
oxylamines under Cu(I) catalysis. This reaction is also helpful for
the synthesis of some quinones bearing annelated N-heterocyclic
natural products.
9. (a) Chen, Y.-L.; Lee, M.-H.; Wong, W.-Y.; Lee, A. W. M. Synlett 2006, 2510; (b)
Chen, Z.; M€uller, P.; Swager, T. M. Org. Lett. 2006, 8, 273; (c) Rincon, R.; Plumet,
J. Synlett 2008, 911.
10. (a) Mi, B.-X.; Wang, P.-F.; Liu, M.-W.; Kwong, H.-L.; Wong, N.-B.; Lee, C.-S.; Lee,
S.-T. Chem. Mater. 2003, 15, 3148; (b) Ding, Y.; Hay, A. S. J. Polym. Sci. Part A:
Polym. Chem. 1999, 3293, 37; (c) Gauvin, S.; Santerre, F.; Dodelet, J. P.; Ding, Y.;
Hlil, A. R.; Hay, A. S.; Anderson, J.; Armstrong, N. R.; Gorjanc, T. C.; D‘Iorio, M.
Thin Sold Films 1999, 353, 218; (d) Matuszewski, B. K.; Givens, R. S.;
Srinivasachar, K.; Carlson, R. G.; Higuchi, T. Anal. Chem. 1987, 59, 1102; (e)
Zweig, A.; Metzler, G.; Maurer, A.; Roberts, B. G. J. Am. Chem. Soc. 1967, 89, 4091.
11. (a) Frincke, J. M.; Faulkner, D. J. J. Am. Chem. Soc. 1982, 104, 265; (b) Parker, K.
A.; Cohen, I. D.; Padwa, A.; Dent, W. Tetrahedron Lett. 1984, 25, 4917.
12. Stipanovic, R. D.; Zhang, J.; Bruton, B. D.; Wheeler, M. H. J. Agric. Food Chem.
2004, 52, 4109.
13. (a) Boven, E.; Erkelens, C. A. M.; Luning, M.; Pinedo, H. M. Br. J. Cancer 1990, 61,
709; (b) Healy, M. P.: Giblin, G. M. P.; Price, H. S. PCT Int. Appl. 2007, WO
2007088189.
14. (a) Hui, B. W.-Q.; Chiba, S. Org. Lett. 2009, 11, 729; (b) Braun, R. U.; Zeitler, K.;
Muller, T. J. J. Org. Lett. 2001, 3, 3297; (c) Martin, R.; Larsen, C. H.; Cuenca, A.;
Buchwald, S. L. Org. Lett. 2007, 9, 3379; (d) Cacchi, S.; Febrizi, G.; Filisti, E. Org.
Lett. 2008, 10, 2629; (e) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 7079.
Acknowledgments
S.N. thanks CSIR, New Delhi for the fellowship. D.S.T. is also
thanked for providing funds for the project and creating 400 MHz
NMR facility under the IRPHA program.
Supplementary data
Supplementary data (detailed experimental procedures and
spectral data for the compounds 2a–2h) associated with this Letter
can be found, in the online version, at doi:10.1016/j.tetlet.2011.
09.070.
15. (a) Sole, D.; Serrano, O. J. Org. Chem. 2010, 75, 6267; (b) Claessens, S.; Jacobs, J.;
Aeken, S. V.; Tehrani, K. A.; De Kimpe, N. J. Org. Chem. 2008, 73, 7555; (c)
Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem. Commun. 2006, 661;
(d) Ding, Q.; Wang, B.; Wu, J. Tetrahedron Lett. 2007, 48, 8599; (e) Ding, Q.; Ye,
Y.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 5439; (f) Yeom, H.-S.; Lee, Y.; Lee, J.-E.;
Shin, S. Org. Biomol. Chem. 2009, 7, 4744.
References and notes
16. Yasmin, N.; Ray, J. K. Synlett 2010, 924. and references cited therein..
17. (a) Liang, Y.; Xie, Y.-X.; Li, J.-H. J. Org. Chem. 2006, 71, 379; (b) Li, P.; Wang, L.; Li,
H. Tetrahedron 2005, 61, 8633; (c) Gholap, A. R.; Venkatesan, K.; Pasricha, R.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2005, 70, 4869; (d) Yi, C.;
Hua, R. J. Org. Chem. 2006, 71, 2535; (e) Gelman, D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2003, 42, 5993; (f) Elangovan, A.; Wang, Y.-H.; Ho, T.-I. Org. Lett.
2003, 5, 1841.
1. (a) Gossauer, A. Die Chemie der Pyrrole; Springer: Berlin, Heidelberg, New York,
1974; (b) Gossauer, A. In Houben-Weyl Methoden der Organischen Chemie;
Kreher, R., Ed.; G. Thieme Verlag: Stuttgart, 1994; p 556. Bd. E6a; (c) Gribble, G.
W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, New York, Toronto, Sydney,
Paris, Frankfurt, 1996; Vol. 2, p 207; (d) Sundberg, R. J. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, New York, Toronto, Sydney, Paris, Frankfurt, 1996;
Vol. 2, p 119; (e) Furstner, A. Synlett 1999, 1523.
18. General procedure for the copper catalyzed cyclization: Compound 1 (1 equiv)
and phenylhydroxylamine (1.2 equiv) were placed in a two-neck round bottom
flask and flashed with argon. DMF (5 mL) was added to the reaction mixture.
Then Et3N (1 equiv), CuCl (10 mol %), and H2O (5 equiv) were added and the
reaction mixture was heated at 85–90 °C for 2 h. After cooling, the reaction
mixture was diluted with cold water and extracted with ether (30 mL Â 3) and
the combined organic layer was dried over anhydrous Na2SO4. The solvent was
evaporated and the crude product was purified by column chromatography.
Spectral data of representative compounds: (1,3-Diphenyl-1H-pyrrol-2-yl)-
phenylmethanone (2a): red solid; yield: 82%; mp 116–118 °C; Rf = 0.3 (silica
gel, petroleum ether:EtOAc 10:1); 1H NMR (CDCl3, 200 MHz): 6.50 (d, 1H,
J = 2.8 Hz), 7.08–7.24 (m, 10H), 7.28–7.34 (m, 4H), 7.66 (d, 2H, J = 7.2 Hz); 13C
NMR (CDCl3, 50 MHz): 110.8, 125.4 (2C), 126.6, 127.4, 127.6, 127.9 (2C), 128.0
(2C), 128.6, 129.2 (2C), 129.3 (2C), 130.0 (2C), 132.3, 133.7, 135.3, 138.5, 140.5,
188.3; Anal. Calcd for C23H17NO: C: 85.42, H: 5.30, N: 4.33. Found: C: 85.34, H:
5.38, N: 4.25; HRMS Calcd for C23H18NO+ [M++H]: 324.14, found: 324.1404.
2. MacDiarmid, A. G. Synth. Met. 1997, 84, 27.
3. Daidone, G.; Maggio, B.; Schillaci, D. Pharmazie 1990, 45, 441.
4. (a) Almerico, A. M.; Diana, P.; Barraja, P.; Dattolo, G.; Mingoia, F.; Loi, A. G.;
Scintu, F.; Milia, C.; Puddu, I.; La Colla, P. Farmaco 1998, 53, 33; (b) Almerico, A.
M.; Diana, P.; Barraja, P.; Dattolo, G.; Mingoia, F.; Putzolu, M.; Perra, G.; Milia,
C.; Musiu, C.; Marongiu, M. E. Farmaco 1997, 52, 667.
5. (a) Kimura, T.; Kawara, A.; Nakao, A.; Ushiyama, S.; Shimozato, T.; Suzuki, K.
PCT Int. Appl. WO 0001688 A1 20000113, 2000.; (b) Kaiser, D. G.; Glenn, E. M. J.
Pharm. Sci. 1972, 61, 1908.
6. Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfond, J.-M.
Eur. J. Med. Chem. 1999, 34, 991.
7. (a) Kawai, A.; Kawai, M.; Murata, Y.; Takada, J.; Sakakibara, M. PCT Int. Appl.
WO 9802430 A1 19980122, 1998.; (b) De Laszlo, S. E.; Liverton, N. J.; Ponticello,
G. S.; Selnick, H. G.; Mantlo, N. B. U.S. Patent 5837719 A 19981117, 1998.; (c)
De Laszlo, S. E.; Liverton, N. J.; Ponticello, G. S.; Selnick, H. G.; Mantlo, N. B. U.S.
Patent 5792778 A 19980811, 1998.; (d) De Laszlo, S. E.; Chang, L. L.; Kim, D.;
Mantlo, N. B. PCT Int. Appl. WO 9716442 A1 19970509, 1997.
ꢀ
19. Crystal data for 2f: CCDC No. 836651, C21H19NO, M = 301.37, triclinic, P1,
a = 7.7853(17) Å, b = 10.173(2) Å, c = 11.267(3) Å,
a = 93.558(6), b = 104.572(6),
V = 107.809(6) Å3, Z = 2, Dcal (mg/m3) = 1.231, 2260 reflections out of 3783
unique reflections with I > 2
wR2 = 0.2075.
r(I), 1.89 < h < 28.52, final R-factors R1 = 0.0542,
8. (a) Maekawa, E.; Suzuki, Y.; Sugiyama, S. Chem. Ber. 1968, 101, 847; (b)
Matsuzawa, Y.; Ichimura, K.; Kudo, K. Inorg. Chim. Acta 1998, 277, 151; (c) Lash,