Direct Synthesis of Pyrroles by Dehydrogenative Coupling of Diols and Amines Catalyzed by Cobalt Pincer Complexes

Article abstract of DOI:10.1002/anie.201607742

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

Full text of DOI:10.1002/anie.201607742

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International Edition: DOI: 10.1002/anie.201607742
German Edition: DOI: 10.1002/ange.201607742
Dihydrogenative Coupling
Hot Paper
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
David Milstein*
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
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201607742.
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Figure 1. a) Known Co-catalyzed dehydrogenation and dehydrogenative coupling reactions. b) Co pincer complexes explored in this study for
pyrrole synthesis.
Table 1: Optimization of the reaction conditions for the dehydrogenative
coupling of 2,5-hexanediol and heptylamine.
formation of pyrrole at 1508C (Table 1, entry 5), probably due
to steric effects, whereas isopropyl-substituted catalyst 2b
produced 21% of N-heptyl-2,5-dimethylpyrrole (entry 6) and
complex 3 yielded 77% of the pyrrole (entry 7). However, the
yield of pyrrole was only 4% when the bipyridine-based
complex 4 was used (entry 8). Therefore the best-performing
complex 1 was chosen for further optimization studies.
Exploring the effect of various bases, KHMDS, NaOEt,
and KH were employed under similar reaction conditions
giving decent yields of pyrroles (entries 9–11). Further testing
revealed that in the absence of NaHBEt3, using 5 mol% of
pre-catalyst 1 and 5 mol% tBuOK at 1208C, no conversion
was observed (entry 12), in the absence of base, using 5 mol%
NaHBEt3 and 5 mol% of 1, only 16% of N-heptyl-2,5-
dimethylpyrrole were obtained (entry 13), and in the absence
of both tBuOK and NaHBEt3, no reaction took place
(entry 14). The aforementioned experiments indicate that
both NaHBEt3 and tBuOK play crucial roles in generating the
catalytically active species. However, higher loading of either
of them (tBuOK or NaHBEt3) (to 10 mol%) under otherwise
identical conditions did not significantly improve the yield of
pyrrole (entries 15 and 16). Changing the solvent to 1,4-
dioxane instead of toluene at 1208C did not have a significant
effect (entry 17). It is worth mentioning at this point that the
difference in 2,5-hexanediol conversion and yield of pyrrole
as observed in Table 1 indicates formation of a mixture of
unindentified products resulting from 2,5-hexanediol. Also
formation of small amounts of N-heptylidene-1-heptylamine
and N-heptyl-1-heptylamine was detected by GC-MS, most
likely as a result of dehydrogenative coupling of unreacted
heptylamine catalyzed by Co.[27] The formation of N-heptyl-
idene-1-heptylamine was further confirmed by performing
a separate reaction of heptylamine in the absence of 2,5-
hexanediol using 5 mol% of complex 1, 5 mol% NaHBEt3,
and 5 mol% tBuOK giving 45% of N-heptylidene-1-heptyl-
amine after 24 h at 1508C. However, the diamine N-heptyl-1-
heptylamine was not observed in this case.
Entry[a]
Cat.
x
Base (y)
T [8C]
Conv[b]
[%]
Yield[b]
[%]
1
2
1
1
1
1
2a
2b
3
4
1
1
1
1
1
1
1
1
1
5
5
5
5
5
5
5
5
5
5
5
–
5
–
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
KHMDS (5)
NaOEt (5)
KH (5)
tBuOK (5)
–
–
tBuOK (5)
tBuOK (10)
tBuOK(5)
120
150
reflux
150
150
150
150
150
150
150
150
120
120
120
120
120
120
99
99
99
99
0
82
99
66
99
99
99
0
99
0
99
99
99
74
92[c]
71
40
0
3[d]
4[e]
5
6
7
8
9
10
11
12
13
14
15
16
17[f]
21
77[c]
4
85[c]
79[c]
90[c]
0
16
0
72
70
71
10
5
5
[a] Conditions: 2,5-hexanediol (0.5 mmol), heptylamine (0.5 mmol), and
dry toluene (2 mL) heated in a closed Teflon Schlenk tube at 120 or
1508C bath temperature in the presence of 4 ꢀ molecular sieves.
[b] Yields and conversions determined by GC and conversion based on
2,5-hexanediol consumption. [c] Yield of isolated product. [d] The
reaction was carried out in an open system under N2 atmosphere while
refluxing. [e] The reaction was carried out in the absence of molecular
sieves. [f] The reaction was carried out using 1,4-dioxane as the solvent.
(GC) revealed the formation of H2. A reaction carried out in
an open system in refluxing toluene in the presence of
molecular sieves generated 71% of the pyrrole product
(entry 3) indicating that the reaction is not affected signifi-
cantly by the presence of hydrogen in the closed system.
However, in the absence of molecular sieves in the closed
system, a lower yield of pyrrole (40%) was obtained under
otherwise similar condition (entry 4).
Using the optimized reaction conditions, the scope of this
base-metal-catalyzed dehydrogenative coupling reaction was
probed with 2,5-dihydroxyhexane and different amines. As
shown in Table 2, various linear primary alkyl amines coupled
with dehydrogenated 2,5-hexanediol to yield the correspond-
ing 1,2,5-substituted pyrroles in excellent yields (Table 2,
entries 1–4).
Our previously reported PNP– and PNN–Co dihalo
complexes 2,[25] 3,[22a] and 4[26] (Figure 1b) were then screened.
Surprisingly, tBu-substituted complex 2a did not show any
2
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Table 2: Dehydrogenative coupling of diols and various amines cata-
lyzed by complex 1.
The reaction between 2,5-hexanediol and cyclohexyl-
amine gave 70% yield of 1-cyclohexyl-2,5-dimethylpyrrole
(entry 5). Similarly, 62% yield of N-phenethyl-2,5-dimethyl-
pyrrole was obtained from 2,5-hexanediol and 2-phenethyl-
amine (entry 6). Exploring the scope further, reactions of 2,5-
hexanediol with various benzylamines were studied, resulting
in moderate to good yields (entries 7–9). On the other hand
dehydrogenative coupling of less basic 4-trifluoromethylben-
zylamine with 2,5-hexanediol resulted in an only moderate
60% yield of the pyrrole (entry 10). Reaction of the less
nucleophilic anilines with 2,5-hexanediol resulted in low
yields (entries 11 and 12).
Entry[a] Diol
Amine (RNH2)
t [h] Yield of pyrrole [%]
1
24 88[b]
However, 2,5-hexanediol dehydrogenatively coupled with
(1-naphthylmethyl)amine to yield the corresponding 1,2,5-
substituted pyrrole in 78% yield (entry 13). The catalytic
performance of 1 in the dehydrogenative coupling of 1,4-
diphenyl-1,4-butanediol and heptylamine was also checked,
producing a moderate 56% yield of 1-heptyl-2,5-diphenyl-
pyrrole (entry 14). Dehydrogenative coupling of primary 1,4-
butanediol with heptylamine resulted in 1-heptylpyrrole in
58% yield as observed by GC-MS (entry 15) along with other
as yet unidentified products.[17]
Regarding the nature of the active cobalt catalyst, we
previously reported that treatment of complex 1 with one
equiv of NaHBEt3 at room temperature gave the para-
magnetic complex (PNNH)CoICl, characterized by X-ray
crystallography.[22a] This CoI complex was prepared and
isolated separately and tested in the dehydrogenative cou-
pling of 2,5-hexanediol and heptylamine. Using 5 mol% of
(PNNH)CoICl and 5 mol% tBuOK at 1508C yielded 86% of
N-heptyl-2,5-dimethylpyrrole after 24 h, which is comparable
to the results obtained when using CoII complex 1 in the
presence of NaHBEt3 and tBuOK (Table 1, entry 2). This
suggests that the actual catalyst is a CoI complex. However,
attempts to isolate the active CoI catalyst by treating
(PNNH)CoICl with one equiv of tBuOK failed. We also
could not isolate an in situ generated intermediate in the
reactions. Nevertheless, we believe that under the reaction
conditions, a mono-deprotonated CoI complex is formed by
2
3
24 93[b]
24 86[b]
24 90[b]
24 70[b]
24 62[b]
24 89[b]
36 68[b]
24 87[b]
24 60[b]
36 25[c]
36 22[c]
4
5
6
7
8
9
10
11
12
À
dehydrohalogention via either the N H or the methylene
proton of the N-arm of the pincer ligand. The unique feature
of the metal complexes developed with the PNNH ligand is
that they have the potential for metal–ligand cooperation by
both amine–amide and aromatization–dearomatization
ligand transformations.[28] The possibly generated highly
unsaturated CoI complex is anticipated to be stabilized by
potential binding with alcohol giving an alkoxy– CoI complex,
which could undergo dehydrogenation under the catalytic
conditions to give the ketone, liberating H2. The ketone
subsequently could couple with the present amine and form
the N-substituted pyrrole and water in a Paal–Knorr con-
densation (Scheme 1). This step was confirmed by a separate
experiment starting from 2,5-hexanedione with heptylamine
at 1508C in the absence of catalyst, quantitatively yielding the
corresponding N-heptyl-2,5-dimethylpyrrole. However, dehy-
drogenation of 2,5-hexanediol in the absence of an amine
resulted in a mixture of unidentified products, not including
2,5-hexanedione. Nevertheless, the ability of catalyst 1 in the
dehydrogenation of a secondary alcohol was demonstrated
13
36 78[b]
14
15
36 56[c]
24 58[c]
[a] Conditions: diol (0.5 mmol), amine (0.5 mmol), toluene (2 mL), and
4 ꢀ molecular sieves heated in an closed Schlenk tube for the specified
time. [b] Yield of isolated product. [c] Yield determined by GC.
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Acknowledgements
This research was supported by the Israel Science Foundation
and by the MINERVA foundation. D.M. holds the Israel
Matz Professorial Chair. P.D. is thankful to Planning and
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Keywords: cobalt · dehydrogenative coupling ·
pincer complexes · pyrroles
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Revised: September 20, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Dihydrogenative Coupling
P. Daw, S. Chakraborty, J. A. Garg,
Y. Ben-David,
D. Milstein*
&&&& — &&&&
A complex of an earth-abundant metal is
shown to catalyze the dehydrogenative
coupling of diols and amines to form
substituted pyrroles with liberation of H2
and water. Of the well-defined PNNH–Co
pincer complexes tested in the presence
of tBuOK and NaHBEt3 complex 1 turned
out to be the most effective. The reaction
is applicable to a wide range of primary
alkyl amines, benzylic amines, and aro-
matic amines, and to primary and sec-
ondary diols.
Direct Synthesis of Pyrroles by
Dehydrogenative Coupling of Diols and
Amines Catalyzed by Cobalt Pincer
Complexes
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!