Cu (I)-catalyzed synthesis of polysubstituted pyrroles from dialkyl ethylenedicarboxylates and β-enamino ketones or esters in the presence of O2

Article abstract of DOI:10.1021/jo101022k

(Figure presented) A straightforward method for the synthesis of polysubstituted pyrroles was achieved easily from oxidative cyclization of β-enamino ketones or esters and alkynoates catalyzed by CuI in the presence of O₂.

Full text of DOI:10.1021/jo101022k

pubs.acs.org/joc
methods for the synthesis of polysubstituted pyrroles
Cu (I)-Catalyzed Synthesis of Polysubstituted
Pyrroles from Dialkyl Ethylenedicarboxylates and
β-Enamino Ketones or Esters in the Presence of O2
included the classical Knorr reaction,5 Hantzsch reaction,6
and Paal-Knorr condensation reaction.7 Recently, new
approaches based on the multicomponent coupling8 and
cycloisomerization of alkyne- and allene-containing sub-
strates catalyzed by a transition metal9 have been developed
and have drawn extensive and enduring attention. Despite
numerous diverse approaches toward the synthesis of poly-
substituted pyrroles have been developed,10 a easy and
efficient synthetic method still remains an attractive goal.
Oxygen is a very ideal oxidant and in attractive to chemists
in terms of its numerous advantages in industry.11 With the
development of the C-H activation12 and in view of the
increased attention to environmental problems, new meth-
ods of using oxygen to construct heterocycles with simple
and readily accessible substrates are highly desirable and
urgent because of its economic, sustainable, and environ-
mentally friendly features.13 As a part of our continuing
study on the utilization of oxygen in organic chemistry,14
Ru-Long Yan, Jia Luo, Chuan-Xin Wang, Chao-Wei Ma,
Guo-Sheng Huang,* and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, People’s Republic
of China
hgs@lzu.edu.cn; liangym@lzu.edu.cn
Received May 25, 2010
(5) (a) Knorr, L. Chem, Ber. 1884, 17, 1635. (b) Manley, J. M.; Kalman,
M. J.; Conway, B. G.; Ball, C. C.; Havens, J. L.; Vaidyanathan, R. J. Org.
Chem. 2003, 68, 6447. (c) Shiner, C. M.; Lash, T. D. Tetrahedron 2005, 61,
11628.
(6) (a) Hantzsch, A. Ber. 1890, 23, 1474. (b) Matiychuk, V. S.; Martyak,
R. L.; Obushak, N. D.; Ostapiuk, Y. V.; Pidlypnyi, N. I. Chem. Heterocycl.
Compd. 2004, 40, 1218. (c) Matiychuk, V. S.; Martyack, R. L.; Obushak,
N. D.; Ostapiuk, Y. V.; Pidlypnyi, N. I. Chem. Heterocycl. Compd. 2004, 40,
1218.
A straightforward method for the synthesis of polysub-
stituted pyrroles was achieved easily from oxidative cycli-
zation of β-enamino ketones or esters and alkynoates
catalyzed by CuI in the presence of O2.
(7) (a) Paal, C. Ber. 1885, 18, 367. (b) Chen, J.; Wu, H.; Zheng, Z.; Jin, C.;
Zhang, X.; Su, W. Tetrahedron Lett. 2006, 47, 5383. (c) Minetto, G.;
Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277.
(8) (a) Cadierno, V.; Gimeno, J.; Nebra, N. Chem.;Eur. J. 2007, 13,
9973. (b) Tejedor, D.; Gonzales-Cruz, D.; Garcia-Tellado, F.; Marrero-
Tellado, J. J.; Rodriguez, M. L. J. Am. Chem. Soc. 2004, 126, 8390.
(c) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am. Chem.
Soc. 2005, 127, 10804. (d) Liu, X.; Huang, L.; Zheng, F.; Zhan, Z. Adv. Synth.
Catal. 2008, 350, 2778. (e) Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007,
129, 12366. (f) Lu, Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430.
(g) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12, 312. (h) Dey, S.; Pal, C.;
Nandi, D.; Giri, V. C.; Zaidlewicz, M.; Krzeminski, M.; Smentek, L.; Hess,
B. A.; Gawronski, J.; Kwit, M.; Babu, N. J.; Nangia, A.; Jaisankar, P. Org.
Lett. 2008, 10, 1373. (i) Alizadeh, A.; Hosseinpour, R.; Rostamnia, S.
synthesis 2008, 2462.
As the most prevalent heterocyclic compounds,1 polysub-
stituted pyrroles are playing increasingly important roles as
synthetic building blocks,2 pharmacophores,3 and various
kinds of functional materials.4 Consequently, they have
drawn considerable interest for synthetic chemists. Classical
(1) (a) Sundburg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 2, p 119. (b) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.;
Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (c) Bullington., J. L.; Wolff, R. R.;
Jackson, P. F. J. Org. Chem. 2002, 67, 9439. (d) F€urstner, A. Angew. Chem., Int.
Ed. 2003, 42, 3582. (e) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(f) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.; Wong, D. J. Eur. J.
Org. Chem. 2006, 3043. (g) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones,
A. Nat. Prod. Rep. 2006, 23, 517. (h) Aiello, A.; D'Esposito, M.; Fattorusso, E.;
Menna, M.; Mueller, W. E. G.; Perovic-Ottstadt, S.; Schroeder, H. C. Bioorg.
Med. Chem. 2006, 14, 17. (i) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem.
Rev. 2008, 108, 264.
(9) (a) Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org.
Lett. 2004, 6, 2957. (b) Ishikawa, T.; Aikawa, T.; Watanabe, S.; Saito, S. Org.
Lett. 2006, 8, 3881. (c) Hiroya, K.; Matsumoto, S.; Ashikawa, M.; Ogiwara,
K.; Sakamoto, T. Org. Lett. 2006, 8, 5349. (d) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (e) Mihovilovic, M. D.;
Stanetty, P. Angew. Chem., Int. Ed. 2007, 46, 3612. (f) Shu, X.; Liu, X.; Xiao,
H.; Ji, K.; Guo, L.; Liang, Y. Adv. Synth. Catal. 2008, 350, 313. (g) Kel’in,
A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(h) Robinsona, R. S.; Dovey, M. C. Tetrahedron Lett. 2004, 36, 6787.
ꢀ
(i) Harrison, T. J.; Kozak, J. A.; Corbella-Pane, M.; Dake, G. R. J. Org.
Chem. 2006, 71, 4525.
(10) (a) Science of Synthesis: Fully Unsaturated Small-Ring Heterocycles
and Monocyclic Five-Membered Hetarenes with One Heteroatom; Maas, G.;
Thieme: Stuttgart, New York, 2000; Vol. 9. (b) Balme, G. Angew. Chem., Int. Ed.
2004, 43, 6238. (c) Wang, J.; Wang, X.; Yu, Z.-S.; Yu, W. Adv. Synth. Catal.
2009, 351, 2063. (d) Lu, Y.; Fu, X.; Chen, H.; Du, X.; Jia, X; Liu, Y. Adv. Synth.
Catal. 2009, 351, 129. (e) Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75,
1674. (f) Lu, Y.; Arndtsen., B. A. Org. Lett. 2009, 11, 1369. (g) Saito, A.; Konishi,
(2) (a) Jones, R. A. Pyrroles, Part II, The Synthesis Reactivity and Physical
Properties of Substituted Pyrroles; Wiley: New York, 1992. (b) Pelkey, E. T.
Prog. Heterocycl. Chem. 2005, 17, 109.
(3) (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996;
Vol. 2, p 207. (b) Hall, A.; Atkinson, S.; Brown, S. H.; Chessell, I. P.; Chowdhury,
A.; Giblin, G. M. P.; Goldsmith, P.; Healy, M. P.; Jandu, K. S.; Johnson, M. R.;
Michel, A. D.; Naylor, A.; Sweeting, J. A. Bioorg. Med. Chem. Lett. 2007, 17,
1200. (c) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213. (d) Clark, B. R.;
Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H. Org. Lett. 2006, 8, 701.
(4) (a) Electronic Materials: The Oligomer Approach; Mu€llen, K., Wegner,
G., Eds.; Wiley-VCH: Weinheim, 1997. (b) Deronzier, A.; Moutet, J.-C. Curr.
Top. Electrochem. 1994, 3, 159. (c) Higgins, S. Chem. Soc. Rev. 1997, 26, 247.
For recent reports, see: (d) Yamaguchi, S.; Tamao, K. J. Organomet. Chem. 2002,
653, 223. (e) Domingo, V. M.; Aleman, C.; Brillas, E.; Julia, L. J. Org. Chem.
2001, 66, 4058.
ꢀ
T.; Hanzawa, Y. Org. Lett. 2010, 12, 372. (h) Tejedor, D.; Lopez-Tosco, S.;
ꢀ
Gonzalez-Platas, J.; García-Tellado, F. Chem.;Eur. J. 2009, 15, 838.
(11) For some reviews, see: (a) Punniyamurthy, T.; Velusamy, S.; Iqbal
J. Chem. Rev. 2005, 105, 2329. (b) Stahl, S. S. Angew. Chem., Int. Ed. 2004,
43, 400.
(12) Li, C.-J. Acc. Chem. Res. 2009, 42, 2335 and references therein.
(13) (a) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243. (b) Shi, Z.; Zhang,
C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
4572. (c) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7895.
DOI: 10.1021/jo101022k
r
Published on Web 06/30/2010
J. Org. Chem. 2010, 75, 5395–5397 5395
2010 American Chemical Society

Yan et al.
JOCNote
herein we wish to report an efficient method to synthesize
polysubstituted pyrroles in thepresence of O2.
obtained in 75% yield in the reaction catalyzed by CuI after
4 h. When O2 was employed as the oxidant, to our delight,
83% of 3aa was isolated (Table 1, entry 2). By increasing the
temperature to 110 °C, the yield had a slight change (Table 1,
entry 3). When the reaction was carried out at 60 °C,
compound 3aa was isolated in only 52% yield (Table 1, entry
4). Among the metal salts we examined, CuI showed the
highest activity for this reaction (Table 1, entries 5-9). In
addition, without metal salts as catalyst, no desired product
was obtained (Table 1, entry 10). Other organic and inor-
Initially, we examined the reaction of (Z)-1,3-diphenyl-
3-(phenylamino)prop-2-en-1-one (1a) and dimethyl but-2-
ynedioate (2a) using air as the oxidant in DMF at 80 °C
(Table 1, entry 1). Gratifyingly, the desired dimethyl 4-ben-
zoyl-1,5-diphenyl-1H-pyrrole-2,3-dicarboxylate (3aa) was
TABLE 1. Optimization of Reaction Conditionsa
t
ganic oxidants such as BuOOH, H2O2, PhI(OAc)2, and
mCPBA were also evaluated, and no improved result was
obtained (Table 1, entries 11-14). Therefore, oxygen was
proved to be the most efficient oxidant in this reaction.
Furthermore, changing the solvent to toluene, THF, or
CH3CN failed to improve the yields (Table 1, entries
15-17). The results indicated that the choice of DMF as
solvent was crucial for the reaction. Ultimately, optimized
conditions were identified, which provided 3aa in good yield
(Table 1, entry 2).
entry
catalyst
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu(OTf)2
Cu(OAc)2 O2
FeCl2
oxidant
air
solvent
temp (°C) yield (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
110
60
80
80
80
80
80
80
80
80
80
80
80
80
80
75
83
82
52
80
70
51
66
27
O2
O2
O2
O2
O2
O2
SCHEME 1. Reaction of the Substrates of 1k and 2b
9
O2
O2
10
11b
12b
13b
14b
15
16
17
CuI
CuI
CuI
CuI
CuI
CuI
CuI
tBuOOH
H2O2
tr
15
PhI(OAc)2 DMF
mCPBA
O2
O2
DMF
11
tr
17
13
toluene
THF
CH3CN
O2
aReaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalysts (0.03
mmol) in 2 mL of solvent for 4 h under oxygen (1 atm). bReactions were
carried out with oxidant (2.0 equiv) under nitrogen.
TABLE 2. Synthesis of Polysubstituted Pyrroles from Dialkyl Ethylenecarboxylates and β-Enamino Ketones or Estersa
1
2
entry
R1
R2
R3
R4
product
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1a
1c
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MeO-Ph
p-MeO-Ph
p-Me-Ph
p-Cl-Ph
Ph
Ph
Me
Me
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
Ph
m-Me-Ph
Ph
Me
OEt
Ph
Ph
Ph
Ph
Ph
2a
2a
2a
2a
2a
2b
2b
2b
2a
2b
2a
2a
2b
2b
Me
Me
Me
Me
Me
Et
Et
Et
Me
Et
3aa
3ba
3ca
3da
3ea
3ab
3cb
3fb
3fa
3gb
3ha
3ia
83
80
81
46
56
85
87
85
82
87
75
64
41
52
9
1f
10
11
12
13b
14b
1g
1h
1i
1j
1k
Ph
Ph
Me
Me
Me
Me
Et
m-Cl-Ph
n-Bu
cyclohexanyl
3jb
3kb
Et
aReaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), CuI (0.03 mmol), O2 (1 atm), 2 mL DMF, 80 °C, 4 h. bThe reactions were carried out at 120 °C
for 8 h.
5396 J. Org. Chem. Vol. 75, No. 15, 2010

Yan et al.
JOCNote
SCHEME 2. Plausible Reaction Mechanism
Having the optimized condition, we then extended the
scope of this reaction, and the results are illustrated in Table 2.
Generally, the reaction of β-enamino ketones or esters with
dialkyl ethylenecarboxylates proceeded smoothly and led to
the desired product 3 in moderate to good yields. To our
delight, this reaction can also tolerate a broad substituents
range of β-enamino ketones or esters (Table 2, entries 1-5).
Remarkably, the electron density on the β-enamino ketones
or esters drastically affects the yields of this reaction. For
example, the reaction of 1a with alkynoate afforded 3ab in
87% yield, whereas 1d was converted to 3da only in 45%
yield (Table 2, entries 4 and 6). Moreover, a wide range of
N-substituents were also compatible with the process, which
include functionalized groups, phenyl, and simple alkyl
groups, and the electron-rich N-substituents also can im-
prove the yields of the reaction (Table 2, entries 8-14).
Satisfactorily, when the N-phenyl groups were replaced with
N-alkyl groups, the desired pyrroles could be obtained in
moderate yields at the expense of a higher reaction tempera-
ture and a longer reaction time (Table 2, entries 13 and 14).
Further investigations demonstrated that the meta positions
of the aromatic group of β-enamino ketones can slightly
decrease the yields, which was presumablely caused by
electron effection. The substrates 1b and 1i reacted with 2a
to form the products 3ba and 3ia in 80% and 64% yields,
respectively (Table 2, entries 2 and 12).
It is worth mentioning that when (Z)-4-(cyclohexylamino)-
pent-3-en-2-one 1k and diethyl but-2-ynedioate 2b were
subjected to the optimized reaction conditions, an unex-
pected compound 4a was isolated in 78% yield,15 and the
desired pyrroles 3kb could be successfully obtained in 52%
yield at the 120 °C for 8 h (Scheme 1). So the compound 4a
would be the intermediate of the transformation.
On the basis of the results obtained above, a plausible
mechanism of this reaction is illustrated in Scheme 2. The
first step involved a coupling of the substrates 1 and 2 to
produce the Michael additional intermediate 4. Conversion
configurations existed between the intermediate 4 and 5 due
to high temperature. Then, the intermediate 6 was generated
by the hydride abstraction with oxidant from the intermedi-
ate 5. Meanwhile, Cu(I) was oxidized to Cu(II), and oxygen
was transformed to OOH-. Sequently, the intermediate 7 is
formed from the intermediate 6 through radical addition.
Finally, the pyrrole 3 results from the dehydrogenation
process with the generation of hydrogen peroxide. In addi-
tion, Cu(II) was reduced to Cu(I) which entered to the next
catalytic cycle.
In conclusion, we have developed a direct method for the
construction of polysubstituted pyrroles. Variation of
N-substituents, aromatic ring, alkyl, and ester was proven
possible, and this reaction can proceed smoothly in moderate
to good yields. In this procedure, molecular oxygen was used
as the oxidant in the synthesis of polysubstituted pyrroles.
Experimental Section
Typical Procedure for the Synthesis of Dimethyl 4-Benzoyl-
1,5-diphenyl-1H-pyrrole-2,3-dicarboxylate (3aa). An oven-dried
Schlenk tube was charged with CuI (5.7 mg, 0.03 mmol), (Z)-
1,3-diphenyl-3-(phenylamino)prop-2-en-1-one (1a, 90 mg, 0.30
mmol), and dimethyl but-2-ynedioate (2a, 43 mg, 0.30 mmol).
The Schlenk tube was sealed and then evacuated and backfilled
with oxygen (3 cycles). Then 2 mL of DMF was added to the
reaction system. The reaction was stirred at 80 °C under O2 (1
atm) for 4 h. After cooling to room temperature, the solvent
diluted with 10 mL of ethyl acetate, washed with 5 mL of brine,
and dried over anhydrous Na2SO4. After the solvent was
evaporated in vacuo, the residues were purified by column
chromatography, eluting with petroleum ether/EtOAc (5:1) to
afford 109 mg (83%) of dimethyl 4-benzoyl-1,5-diphenyl-1H-
pyrrole-2,3-dicarboxylate (3aa) as a yellow solid, mp 38-40 °C.
1H NMR (400 MHz, CDCl3) δ 7.70-7.68 (m, 2 H), 7.39-7.22
(m, 6 H), 7.15-7.13 (m, 2 H), 7.05-6.95 (m, 5 H), 3.70 (s, 3 H),
3.63 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 191.9, 164.5, 160.5,
139.2, 138.1, 137.1, 132.3, 130.6, 129.2, 129.0, 128.76, 128.72,
128.3, 128.0, 127.9, 127.7, 125.3, 122.5, 121.6, 52.3, 52.0; IR
(neat, cm-1) 2951, 1725, 1661, 1443, 1278, 1220, 1080, 917, 696;
þ
HRMS calcd for C27H22NO5 [M þ H]
440.1492, found
440.1489.
Acknowledgment. We thank the National Science Foun-
dation (NSF-20732002, NSF-20090443, and NSF-20872052)
for financial support.
(14) Yan, R.; Huang, J.; Luo, J.; Wen, P.; Huang, G.; Liang, Y. Synlett
2010, 7, 1071.
Supporting Information Available: Detailed experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
ꢁ
ꢁ
ꢀ
ꢀ
(15) (a) Simunek, P.; Peskova, M.; Bertolasi, V.; Lycka, A.; Machacek, V.
Eur. J. Org. Chem. 2004, 5055. (b) Ali, A. A.; Winzenberg, K. N. Aust. J.
Chem. 2005, 58, 870.
J. Org. Chem. Vol. 75, No. 15, 2010 5397