Angewandte
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Dihydrogenative Coupling
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Direct Synthesis of Pyrroles by Dehydrogenative Coupling of Diols and
Amines Catalyzed by Cobalt Pincer Complexes
Prosenjit Daw+, Subrata Chakraborty+, Jai Anand Garg, Yehoshoa Ben-David, and
Abstract: Herein, the first example of base-metal-catalyzed
dehydrogenative coupling of diols and amines to selectively
form functionalized 1,2,5-substituted pyrroles liberating water
and hydrogen gas as the sole by-products is presented. The
reaction is catalyzed by pincer complexes of earth-abundant
cobalt.
amines, and base was demonstrated by Beller et al.[16] An
interesting dehydrogenative coupling of 2,5-hexanediol and
amines to form pyrroles, albeit in modest yields (45–48%),
catalyzed by a ruthenium complex in the presence of sodium
formate, was developed by Crabtree et al.[17]
However, despite the importance of such elegant methods
for the synthesis of pyrroles employing noble metals, the
development of nonprecious base-metal catalysts would be
a significant advance from the perspective of abundance, cost,
and sustainability.[18] Moreover, precious metals are often
toxic, and potential contamination by particles of these metals
is a significant issue in the pharmaceutical industry. Remark-
able progress has been made in recent years regarding
catalysis by complexes of first-row base metals (Fe, Mn, Ni,
Co).[19–21] For example, several homogeneous cobalt catalysts
were discovered to be effective in the hydrogenation of
olefins,[21a,f] imines,[21a] ketones,[21b] and CO2.[21h,i] Recently, we
reported the first ester hydrogenation[22a] and nitrile hydro-
genation[22b] reactions catalyzed by a pyridine-based PNNH–
Co pincer complex. Homogeneous cobalt catalysts have also
been exploited for dehydrogenation and dehydrogenative
coupling reactions. Hanson and Zhang first reported dehy-
drogenation of secondary alcohols and dehydrogenative
coupling of alcohols and amines to form imines, catalyzed
by a cationic PNP–Co pincer complex (Figure 1a).[21b] Jones
et al. described the acceptorless dehydrogenation and hydro-
genation of N-heterocycles using the same catalyst.[23] Very
recently the groups of Kempe,[24a] Zhang,[24b] and Kirchner[24c]
independently reported cobalt-catalyzed amine alkylation
reactions by alcohols (Figure 1a).
Herein, we report a pyrrole synthesis catalyzed for the
first time by a base-metal complex. It involves acceptorless
dehydrogenative coupling of 1,4-substituted 1,4-butanediols
and various amines using a cobalt pincer complex to generate
1,2,5-substituted pyrroles with extrusion of water and H2 as
the only by-products.
Initially, we explored the possibility of pyrrole formation
from diols and amines using our most promising PNNH–Co
precatalyst 1[22a] (Figure 1b). To generate the active species,
the use of one equiv of NaHBEt3 and tBuOK as hydride
source and base, respectively, was envisioned as observed in
our earlier work on PNNH–Co-catalyzed ester and nitrile
hydrogenations.[22]
P
yrroles and their derivatives are valuable intermediates in
the synthesis of numerous natural products, agrochemicals,
flavors, dyes, and functional materials.[1] They also have
antibacterial, antitumor, anti-inflammatory, and antifungal
properties.[2] Polypyrroles are conducting polymers and used
in solar cells[3] and batteries;[4] they can also be used as
antioxidants and gas sensors.[5] The classical methods for
pyrrole synthesis involve the Knorr,[6] Paal–Knorr[7] and
Hantzsch[8] reactions. Lately, metal-catalyzed cyclization[9]
and multicomponent coupling reactions[10] have been devel-
oped for the synthesis of functionalized pyrroles. Although
these protocols are effective, most of them suffer from several
shortcomings, such as poor availability of starting materials,
multi-step synthetic operations, and copious waste genera-
tion.
In terms of sustainable synthesis, an environmentally
benign route to pyrroles from renewable resources would be
highly desirable. In this respect direct access to substituted
pyrroles from readily available feedstocks like alcohols and
polyols is attractive since alcohols are either industrial
products or can be derived from lignocellulosic biomass.[11]
Indeed, notable progress has been made in recent years in
sustainable pyrrole synthesis based on the acceptorless
dehydrogenation of alcohols[12] using complexes based on
the noble metals Ir and Ru.[13] Kempe and Michlik first
reported the efficient synthesis of pyrroles by reaction of
amino alcohols with secondary alcohols catalyzed by triazine–
iridium complexes,[14] and we reported in the same year that
PNN–ruthenium pincer complexes are efficient catalysts for
this reaction.[15] Attractive synthesis of various substituted
pyrroles catalyzed by [Ru3(CO)12]/Xantphos and [RuCl2(p-
cymene)]2/Xantphos systems using ketones, vicinal diols,
[*] Dr. P. Daw,[+] Dr. S. Chakraborty,[+] Dr. J. A. Garg, Y. Ben-David,
Prof. D. Milstein
Department of Organic Chemistry, Weizmann Institute
Rehovot, 76100 (Israel)
E-mail: david.milstein@weizmann.ac.il
Reaction of 2,5-hexanediol with n-heptylamine using
NaHBEt3, tBuOK, and complex 1 in toluene in a closed
system in the presence of 4 ꢀ molecular sieves resulted in the
formation of N-heptyl-2,5-dimethylpyrrole in 74% yield at
1208C and in 92% yield at 1508C after 24 h (Table 1, entries 1
and 2). Analysis of the gas phase by gas chromatography
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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