Cross-dehydrogenative coupling between enamino esters and ketones: Synthesis of tetrasubstituted pyrroles

Article abstract of DOI:10.1021/ol300147t

Tetrasubstituted pyrroles have been synthesized via the cross-dehydrogenative coupling between enamino esters and acetone. Silver carbonate proved to be an effective oxidant, and no transition metal catalyst is necessary.

Full text of DOI:10.1021/ol300147t

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1412–1415
Cross-Dehydrogenative Coupling
between Enamino Esters and Ketones:
Synthesis of Tetrasubstituted Pyrroles
Miao Zhao, Fen Wang, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
P. R. China
xwli@dicp.ac.cn
Received January 19, 2012
ABSTRACT
Tetrasubstituted pyrroles have been synthesized via the cross-dehydrogenative coupling between enamino esters and acetone. Silver carbonate
proved to be an effective oxidant, and no transition metal catalyst is necessary.
Construction of CÀE (E = C, N, and O) bonds via the
oxidative functionalization of CÀH bonds with an EÀH
group has attracted increasing attention over the past
decades.1 This process is especially important in achieving
molecular complexity considering the ubiquity of CÀH
bonds in organic compounds, and these CÀE bonds are
key linkages in organics. Two categories of intrinsic path-
ways can be followed in this process, namely, the
(transition-metal-catalyzed) CÀH activation pathway2
and the cross-dehydrogenative coupling (CDC) pathway.3
While oxidative cross-coupling via the CÀH activation
pathway has been well-studied in terms of scope, mecha-
nisms, and applications, the construction of CÀE bonds
via a CDC process has become an increasingly important
strategy. Given the abundance of CÀH bonds, this strat-
egy represents a step-economic access to CÀC bonds in
that there is no necessity of prefunctionalization of the
CÀH bond in either of the precursors. Previous reports
indicated that metal or organic single-electron oxidants or
combination of metal catalysts and organic oxidants have
been widely used for CDC reactions, among which Fe,4
Cu,5 and V6 catalysts have been well-studied.
The pyrrole ring is widely present in numerous natural
products, synthetic pharmaceuticals, and molecular
metarials. Therefore, considerable attention has been paid to
develop efficient methods for the synthesis of these privi-
leged molecules. In recent years, a large number of redox-
neutral or oxidative pyrrole syntheses have indeed been
reported.7 While pyrroles and indoles are indeed different,
we reason that inspirations on pyrrole synthesis can be
(4) (a) Li, Y.; Li, B.; Lu, X.; Lin, S.; Shi, Z. Angew. Chem., Int. Ed.
2009, 48, 3817. (b) Park, S. J.; Price, J. R.; Todd, M. H. J. Org. Chem.
2012, 77, 949. (c) Chandrasekharam, M.; Chiranjeevi, B.; Gupta,
K. S. V.; Sridhar, B. J. Org. Chem. 2011, 76, 10229. (d) Richter, H.;
(1) For reviews, see: (a) Satoh, T.; Miura, M. Chem.;Eur. J. 2010,
16, 11212. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (c) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (d) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem.
Soc. Rev. 2010, 39, 712. (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (f) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (g) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (h) Sun, C.-L.; Li,
B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
~
€
Mancheno, O. G. Org. Lett. 2011, 13, 6066. (e) Ghobrial, M.; Schnurch,
M.; Mihovilovic, M. D. J. Org. Chem. 2011, 76, 8781. (f) Liu, W.; Liu, J.;
Ogawa, D.; Nishihara, Y.; Guo, Y.; Li, Z. Org. Lett. 2011, 13, 6272. (g)
Liu, P.; Zhou, C.- Y.; Xiang, S.; Che, C.-M. Chem. Commun. 2010, 46,
2739.
(5) (a) Richter, H.; Rohlmann, R.; Mancheno, O. G. Chem.;Eur. J.
2011, 17, 11622. (b) Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010,
49, 10181. (c) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075.
(d) Zhao, L.; Basle, O.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2009, 106,
4106.
(2) For a leading review, see:Labinger, J. A.; Bercaw, J. E. Nature
2002, 417, 507.
(6) Alagiri, K. A.; Ravikumara, G. S.; Prabhu, K. R. Chem. Com-
mun. 2011, 47, 11787.
(7) For a review, see:Schmuck, C.; Rupprecht, D. Synthesis 2007,
3095.
(3) For reviews, see: (a) Jones, K. M.; Klussmann, M. Synlett 2012,
159. (b) Li, C.-J.; Yoo, W.-J. Top. Curr. Chem. 2010, 292, 281. (c) Li,
C.-J. Acc. Chem. Res. 2009, 42, 335. (d) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215.
r
10.1021/ol300147t
Published on Web 02/27/2012
2012 American Chemical Society

drawn from the synthesis of related indoles that utilize CDC
reactions. Recent work has shown that palladium(II),8
Fe(III),9 and copper(II)10 can efficiently catalyze the oxidative
cyclization of readily accessible β-enamino esters, affording
indole products via oxidative CÀC coupling. This oxidative
coupling reaction can be alternatively achieved using
PhI(OAc)2 as the sole oxidant.11 Despite these progresses,
(intermolecular) CDC reactions that involve β-enamino esters
are rare, likely due to the competitive intramolecular oxidative
cyclization. In fact, intermolecular CÀC coupling via CDC
reactions are highly desirable in delivering molecular complex-
ity. Very recently, Glorius reported a highly efficient synthesis
of pyrazoles via Cu(II)-catalyzed CDC between a β-enamino
ester and a nitrile, a process that involves CÀC and NÀN
bond formation (Scheme 1).12 We reason that the related
coupling of the two CH bonds in β-enamino ester with an
unactivated methyl ketone that affords a pyrrole is in principle
feasible. However, CDC reactions involving ketones are
rather limited. We now report the efficient synthesis of
tetrasubstituted pyrroles via cross-dehydrogenative coupling
between β-enamino esters and acetone.
In addition, other single-electron oxidants such as FeCl3,
DDQ, CAN, and PhI(OAc)2 only afforded pyrrole 2a in
lower yield. Interestingly, reactions using Ag(I) oxidants
tend to afford the desired product in improved yield. Thus,
when Ag2CO3 (2 equiv) was applied in acetone, the desired
product 2a was generated in 64% GC yield, together with a
small amount of the cyclization product 3a (entry 14). We
found that the equivalence of acetone and Ag2CO3 has
rather large effects on the efficiency and selectivity of this
reaction. When a smaller amount of acetone was used, the
CDC reaction is somewhat lower in both efficiency and
selectivity (entries 8À13). Gratifyingly, when 3 equiv of
Ag2CO3 were provided in a large excess of acetone, the
isolated yield of pyrrole 2a was improved to 70%, although
side product 3a was also obtained (entry 1). Further im-
provement of the selectivity to favor 2a met with failure
when Pd(OAc)2 (10 mol %) was introduced, under which
conditions only indole 3a was isolated (entry 2). It is
noteworthy that this reaction needs to be carried out under
laboratory light, while reactions carried out in the dark
resulted in lower yield and lower selectivity. Hence, the slow
decomposition of Ag2CO3 induced by visible light might
facilitate this reaction so that the reaction is both more
efficient and reproducible under laboratory light. In con-
trast, other silver(I) oxidants proved less effective, and 2a
was generated only in lower yield using AgOAc, AgF,
AgNO3, and Ag2O with or without the extrusion of light.13
Scheme 1. β-Enamino Esters in CDC Reactions
Table 1. Screening of Reaction Conditionsa
yield (%)b
We feel that nitriles and ketones are significantly different
in terms of electrophilicity and nucleophilicity, and coupling
with ketones should expand the chemistry of CDC for
heterocycle synthesis. We embarked on our studies with
the coupling between β-enamino ester 1a and acetone under
oxidative conditions. When Cu(OAc)2 was applied as a
stoichiometric oxidant in acetone (sealed tube, 110 °C), the
desired pyrrole 2a was obtained, albeit in rather low yield
together with traces of the cyclization product indole 3a
(Table 1, entry 7). Product 2a was identified as a tetrasub-
stituted pyrrole on the basis of NMR spectroscopy. In
contrast, switching to other copper(II) oxidants such as
CuCl2 and Cu(OTf)2 failed to give any improved yield.
entry oxidant (equiv) acetone (mL) solvent (mL)
2a
3a
1
Ag2CO3 (3)
Ag2CO3 (3)
AgOAc (3)
AgNO3 (3)
AgF (3)
3
72 (70c) 11
2d
3
3
trace
66
61
3
9
4
3
23
4
5
3
<5
trace
trace
trace
38
6
Ag2O (3)
3
14
7
Cu(OAc)2 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (3)
Ag2CO3 (2)
Ag2CO3 (3)
DDQ (3)
3
17
8
0.5
0.5
0.5
0.5
1
DMF (1.5)
17
9
PhMe (1.5) 18
THF (1.5)
13
10
11
12
13
14
15e
16
17
5
14
MeOH (1.5) 14
45
36
43
64
30
2
23
3
9
(8) Wrtz, S.; Rakshit; Neumann, S. J. J.; Droge, T.; Glorius, F.
Angew. Chem., Int. Ed. 2008, 47, 7230.
(9) Guan, Z.-H.; Yan, Z.-Y.; Ren, Z.-H.; Liu, X.-Y.; Liang, Y.-M.
3
trace
trace
3
CAN (3)
3
Chem. Commun. 2010, 46, 2823.
(10) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew.Chem.
Int. Ed. 2009, 48, 8078.
(11) (a) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417. (b) Du,
Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett. 2006, 8, 5919.
(12) Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed.
2010, 49, 7790.
a Conditions: 1a (0.3 mmol), oxidant, acetone, solvent, 110 °C, sealed
tube under nitrogen, 24 h. b GC yield with 1,3,5-trimethoxybenzene as an
internal standard. c Isolated yield. d Pd(OAc)2 (10 mol %) was added.
e 1.2 equiv of 2,6-di-tert-butyl-4-methyl phenol was added.
Org. Lett., Vol. 14, No. 6, 2012
1413

With the optimized conditions in hand, we next explored
the scope of the enamino ester substrate (Scheme 2).
Substrates with variable N-substituents were examined
first. Electron-donating (2c, 2d, 2h, and 2i), -withdrawing
(2m), and halogen (2g, 2k, and 2l) substitutents at the
ortho, meta, and para positions of the N-aryl group in the
substrateare well-tolerated, and the coupled products were
isolated in yields ranging from 51 to 76%. Moreover, the
N-substitutent is not limited to an aryl group; N-benzyl-
substituted enamino esters, including a sterically hindered
2° benzyl-substituted enamino ester, readily coupled with
acetone in high yields (2n and 2o). The high-yielding
synthesis of these two products is likely ascribed to the
inhibition of the competitive cyclization of the starting
enamino ester. The cyclization, if any, would unfavorably
afford a nonaromatic six-membered heterocycle. The
scope of the substrate in terms of the R1 group in the
enamino ester was further demonstrated. Enamines bear-
ing electron-rich and -poor aryl as well as alkyl (2pÀ2u) R1
groups all underwent smooth coupling with acetone to
afford the desired pyrroles in moderate to high yields,
although somewhat lower yields were obtained for sub-
strates with an alkyl R1 group (2t and 2u).
Scheme 2. Cross-Dehydrogenative Coupling of Enamino Esters
with Acetonea,b
The EWG in the enamino substrate is not limited to an
ester group; a β-enamino ketone also readily coupled with
acetone to give the expected acyl-functionalized pyrrole
(2v). Since acetone is relatively less reactive, we reasoned
that ketones with activated methylene groups should also
undergo this coupling reaction if they are compatible with
the oxidation conditions. Indeed, acetylacetone and a
β-keto ester readily coupled with the enamino ester to afford
fully substituted pyrroles (2w and 2x). We noted that this
coupling between β-dicarbonyl compounds and enamino
esters has been reported using CAN as an oxidant.14
However, CDC reactions and catalytic CÀH activation
of acetone are rare.5b,15,16 Extension of this reaction to
other less reactive ketones such as butanone, however, met
with failure, and the indole cyclization product was iso-
lated as the major one.
a Conditions: enamino ester (0.3 mmol), Ag2CO3 (0.3 mmol), acetone
(3 mL), 110 °C, sealed tube under nitrogen, 24 h.
b Isolated yield.
Several experiments were conducted to probe the reac-
tion mechanism. When 1a was coupled with acetone-d6
under the standard conditions, product 2a-d4 was isolated
in 32% yield, where no deuterium scrambling was detected
2b-d4:3b = 36:64 when acetone-d6 was used. These results
revealed that the CDC and the simple cyclization reactions
always occurred in direct competition. The preference for
simple cyclization in acetone-d6 indicated that the rate of
the CDC reaction is lowered as a result of kinetic isotope
effect. Thus, cleavage of the CÀH bond in acetone should
be involved in the rate-determining step. When the cou-
pling of 1a and acetone was carried out in the presence of
1.2 equiv of a radical inhibitor 2,6-di-tert-butyl-4-methyl
phenol, neither the pyrrole (2a) nor the indole (3a) was
detected in an appreciable amount, indicating the inter-
mediacy of radical species in this reaction. Competition of
two enamino esters 1i and 1l that differ electronically in the
N-aryl group revealed that products 2i and 2l were gener-
ated in nearly equal ratio on the basis of GC analysis. This
result suggests that the reaction is insensitive to the elec-
tronic nature of the N-substituent.
1
on the basis of H NMR spectroscopy. In addition, two
parallel reactions were conducted side by side in acetone
and acetone-d6 (Scheme 3). GC analysis revealed that the
distribution of the products depends on the solvent. In
acetone, pyrrole 2b was detected as the major product with
a ratio of 2b:3b = 82:18. However, the pyrrole 2b-d4 was
observed only as the minor products with a ratio of
(13) For recent examples of CDC reactions using Ag(I) oxidants, see:
(a) Zhang, X.; Liu, B.; Shu, X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem.
2012, 77, 501. (b) Daquino, C.; Rescifina, A.; Spatafora, C.; Tringali, C.
Eur. J. Org. Chem. 2009, 6289. (c) Yin, P.-X.; Cheng, J.-K.; Li, Z.-J.;
Zhang, L.; Qin, Y.-Y.; Zhang, J.; Yao, Y.-G. Inorg. Chem. 2009, 48,
10859.
(14) (a) Chuang, C.-P.; Wu, Y.-L. Tetrahedron 2004, 60, 1841. (b)
Tsai, A.-I.; Chuang, C.-P. Tetrahedron 2006, 62, 2235.
(15) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett. 2010, 12, 5214.
(16) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242.
A plausible reaction mechanism is suggested on the
basis of these preliminary data and literature precedents
1414
Org. Lett., Vol. 14, No. 6, 2012

Scheme 3. Isotope Effects in Acetone
Scheme 4. Plausible Mechanism for Pyrrole Synthesis
process, no transition metal catalyst is necessary, CÀC and
CÀN bonds are effectively constructed, and prefunction-
alization of neither coupling partner is necessary. A broad
scope of enamino ester substrate has been established. This
reaction makes direct use of a simple and abundant three-
carbon feedstock without the requirement of a stoichio-
metric amount additive or preformed enolate. Studies are
directed toward further applications of this method to the
synthesis of other heterocyclic compounds.
(Scheme 4). Single-electron oxidation of the anion of the
β-imino ester tautomer of the substrate generates a radical
intermediate, which is further oxidized by silver(I) to a
carbocation.17 Acetone is proposed to undergo nucleo-
philic addition to this carbocation, leading to CÀC bond
formation. Subsequent intramolecular condensation of
this enamino ketone intermediate affords the final pyrrole
product. It is noteworthy that this mechanism is in sharp
contrast to that proposed in the synthesis of pyrrazoles
starting from β-imino esters and nitriles, where the
β-imino ester acts as a nucleophile that attacks the nitrile.12
In the case of actone, however, the β-imino ester is an
electrophile, where the umpolung is induced by single-
electron oxidation.
Acknowledgment. Financial support from the Dalian
Institute of Chemical Physics, Chinese Academy of
Sciences is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have achieved an efficient and direct
synthesis of substituted pyrroles via the cross-dehydro-
genative coupling of enamino esters with acetone. In this
(17) (a) He, Z.; Li, Z. Chem.;Asian. J. 2011, 6, 1340. (b) He, Z.; Li,
H.; Li, Z. J. Org. Chem. 2010, 75, 4636.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1415