Iron-catalyzed sustainable synthesis of pyrrole

Article abstract of DOI:10.1021/acs.orglett.6b02819

Efficient, sustainable, highly regiospecific substituted pyrroles were synthesized using a well-defined, air stable, molecular iron(0) complex. The developed methodology is broadly applicable and tolerates a variety of functional groups. C-2, C-3, and C-2 & C-4 substituted pyrroles were synthesized in good yield. Symmetrical bis-pyrroles were accessible for the first time using an iron catalyst. On the basis of the experimental observation, we propose that the reaction proceeds through a hydrogen autotransfer process followed by second oxidation/ intramolecular dehydrative condensation to provide the pyrrole.

Full text of DOI:10.1021/acs.orglett.6b02819

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Sustainable Synthesis of Pyrrole
Balakumar Emayavaramban,† Malay Sen,† and Basker Sundararaju*,†
†Fine Chemical Laboratory, Department of Chemistry, Indian Institute of TechnologyKanpur, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: Efficient, sustainable, highly regiospecific substi-
tuted pyrroles were synthesized using a well-defined, air stable,
molecular iron(0) complex. The developed methodology is
broadly applicable and tolerates a variety of functional groups.
C-2, C-3, and C-2 & C-4 substituted pyrroles were synthesized in
good yield. Symmetrical bis-pyrroles were accessible for the first
time using an iron catalyst. On the basis of the experimental
observation, we propose that the reaction proceeds through a hydrogen autotransfer process followed by second oxidation/
intramolecular dehydrative condensation to provide the pyrrole.
starting from amino alcohol and secondary alcohol (Scheme
1a).
ydrogen borrowing or hydrogen auto transfer (HA)
Hreactions catalyzed by transition metals are considered to
be one of the most environmentally benign transformations as
the reactions do not produce any side product except water.1
This well-established concept proceeds through initial
activation of inert substrate (C−X) into reactive intermediate
(C = X) via dehydrogenation assisted by the transition metal,
followed by functional group transformation to produce second
reactive intermediate (C = Y), which will be subsequently
reduced to inert product (C−Y) by the in situ formed metal
hydride to regenerate active catalytic species. Such trans-
formations are currently possible with noble metals, especially
Ru, Ir, and Pd. With advancement of green chemistry and
sustainability, it is now imperative to develop catalysts derived
from metals that are earth abundant, nontoxic, and environ-
mental friendly for challenging C−N bond formation without
any side products.2 Pronounced efforts were witnessed very
recently using first row transition metals for such catalytic
transformations.3 In this regard, the first report for C−N bond
formation starting from alcohol via HA process using well-
defined low valent iron (0) complex4 was reported by Barta and
Feringa5a,d followed by Wills5b and Zhao.5c Due to its inherent
redox property, the iron(0)tricarbonyl complex is widely
known to activate inert substrate via dehydrogenation/hydro-
genation reactions that were reported earlier for C−C bond
formation.6
The significance of polysubstituted pyrroles was exhibited in
many different fields, including pharmaceuticals,7a natural
products,7d dyes,7c and materials,7b which are often challenging
synthetic targets. Although it is possible to synthesize pyrrole
through traditional routes, it suffers from harsh reaction
conditions, multistep synthesis, nonavailability of raw materials,
poor functional group tolerance, and unpredictable regiose-
lectivity.8 To overcome these limitations, modern methods
were developed by employing the hydrogen autotransfer
process. Kempe9 and Milstein10 independently developed the
[Ir]- and [Ru]-based catalytic system for pyrrole synthesis
Scheme 1. General Synthesis of Pyrroles via Hydrogen
Autotransfer
At the same time, similar strategy was reported by Beller for
[Ru]-catalyzed multicomponent catalytic pyrrole synthesis
using the same (HA) process (Scheme 1b).11 While the former
method required a stoichiometric amount of base, the latter
needed a catalytic amount of base to proceed the reaction
toward the product. Tonks et al. first demonstrated a green
synthetic route for the production of polysubstituted pyrroles
through oxidative coupling of alkynes with diazenes via a
Ti(II)/Ti(IV) redox process.12 In our continuous effort on the
development of catalysts based on base metals for sustainable
transformations,13 we envisioned the possibility of iron-
catalyzed pyrrole synthesis starting from buten-1,4-diol and
primary amine (Scheme 1c). We postulate that the initial allylic
amination of buten-1,4-diol 1 with primary amine lead to
intermediate A via HA process which then undergoes second
oxidation of alcohol, leading to intermediate B followed by
Received: September 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02819
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Letter
a
intramolecular condensation and dehydration to pyrroles 3−5,
Table 1. Optimization of Reaction Parameters
as shown in Scheme 2.
Scheme 2. Postulated Catalytic Cycle for Pyrrole Synthesis
b
[M]
additive
Me3NO
solvent
yield (%)
79
1
[Fe]
[Fe]
[Fe]
[Fe]
[Fe]
[Fe]
[Fe]
toluene
toluene
toluene
toluene
CPME
c
2
Me3NO
Me3NO
Me3NO
Me3NO
Me3NO
Me3NO
52
c
c
,
,
d
e
3
52
71
77
44
71
nr
4
5
6
C6H5CF3
m-xylene
toluene
toluene
toluene
toluene
toluene
toluene
7
8
Fe2(CO)9
[CpFe(CO)2]2
[Cp*IrCl2]2
[Ru(p-cym)Cl2]2
Pd/C
9
nr
10
11
12
13
tBuOK
22
29
nr
t
Dppf + BuOK
[Fe]
53
a
All reactions were carried out in an argon atmosphere using 1a/2a/
[Fe]/additive in 0.3/0.45/0.03/0.03 mmol, respectively, in 2 mL of
b
toluene at 150 °C (oil bath temperature) for 24 h. Isolated yield.
Murahashi did the pioneering work using Pd black, which
proceeded through a Pd-catalyzed dehydrogenation/reduction
pathway for allylic amination of (Z)-buten-1,4-diol followed by
Pd-assisted intramolecular cyclization.15 After nearly a decade,
Watanabe reported the same reaction using [Ru] catalyst, albeit
in low yield.16 The catalyst utilized in this reaction is known for
isomerization of double bonds; hence, it was proposed that the
reaction proceeded through an isomerization pathway.
Recently, Williams et al. reported the same reaction with
Ru(II) catalyst to expand the scope of the reaction.17 It is worth
mentioning that the reported reactions are documented only
for nonsubstituted pyrroles starting from commercially available
cis-buten-1,4-diol/butyn-1,4-diol. Herein, we report a novel,
efficient synthesis of pyrrole using an air stable, well-defined
iron(0) catalyst.
c
d
One milliliter of toluene was used. 1a/2a (0.6/0.3 mmol) was used.
e
Fifty milligrams of 4 A° MS was added. CPME = cyclopentylmethyl
ether
Scheme 3. Scope of Amines
We initiated our investigation to get access to C-3 substituted
pyrrole using (E)-2-phenylbut-2-ene-1,4-diol and benzyl amine
as a model substrate along with catalytic amount of [Fe]-
catalyst and Me3NO in 2 mL of toluene at 150 °C for 24 h,
which were standard conditions that are established by us for
allylic amination.13 Under these reaction conditions, 79% of 3-
phenyl-N-benzylpyrrole was isolated (Table 1, entry 1). Neither
changing the concentration nor altering the substrate ratio
improved the product formation (entries 2 and 3). Addition of
molecular sieves has no effect on the reaction (entry 4). Brief
screening of other solvents such as CPME and m-xylene gave
similar yields as entry 1, while α,α,α-trifluorotoluene decreased
the yield of 3a (entries 5−7). Other iron precursors did not
give any product formation (entries 8 and 9). We also
compared the reactivity of some well-known HA catalysts,
which are found to be less efficient under standard reaction
conditions (entries 10−12). Moderate yield of 3a was obtained
when the reaction was performed without any additive (entry
13).
With best conditions in hand, we next examined scope and
limitation of various amines and alcohols. At first, various
amines were tested by keeping (E)-2-phenylbut-2-ene-1,4-diol
as a coupling partner (Scheme 3). o- and p-Substituted benzyl
amines gave expected pyrroles in good yield (3b and c).
Pyridine-2-ylmethanamine, possessing a strong chelating group,
reacted smoothly with moderate yield (3d).
B
DOI: 10.1021/acs.orglett.6b02819
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Letter
Excellent product formation was observed when α-
methylbenzylamine (2e) was used as the amine partner. The
reaction was sluggish when aromatic amines including 2-
aminopyridine were utilized, and moderate yield was obtained
(3f−h). Aliphatic amines such as hexyl, isobutyl, cyclohexyl,
and tert-butyl amines gave moderate to good yield under the
standard conditions (3i−l). β- and γ-amino alcohols were
tested as a primary amine source, and gratifyingly, both gave the
corresponding pyrrole (3m and 3n) selectively without any
oxidation of primary alcohol. Sterically bulkier amine such as
adamantyl amine, medicinally important tryptamine, and
monoprotected 1,2-diphenylethylene diamine were successfully
converted into pyrrole in respectable yield (3o−q). This
extensive scope of amine demonstrates high functional group
tolerance, which includes Br, alcohol, and amide. It is necessary
to mention that, during the preparation of this manuscript,
Barta et al. reported the analogous reaction using a catalytic
amount of iron(0) tricarbonyl complex for nonsubstituted
pyrrole starting from cis-buten-1,4-diol and butyn-1,4-diol.18
We extended this methodology further to the synthesis of
symmetrical bis-pyrrole starting from diamine with excess (E)/
(Z)-diol through a one pot process in satisfactory yield
(Scheme 4).
Scheme 5. Scope of Alcohols
Scheme 4. Symmetrical Bis-pyrrole Synthesis
reactivity was observed with buten-1,4-diol, and nonsubstituted
pyrroles were obtained in decent yield (Scheme 6).
Scheme 6. Synthesis of Pyrrole from Butyn-1,4-diol
We next explored the scope of the various substituted diol 1.
We began our investigation by testing commercially available
cis- and trans-buten-1,4-diol by keeping 4-OMe-benzylamine as
a coupling partner (Scheme 5). Both cis- and trans-isomers gave
the expected pyrroles in good yield, but there is a significant
difference in reactivity, which depends on the stereoisomer of
the starting diol.
For example, cis-buten-1,4-diol gave 81% yield, whereas the
trans-isomer provided only 61% isolated yield of pyrrole 5a
after 30 h. C-3 functionalized pyrroles can be extended to other
functional groups such as p-tolyl-, p-anisyl, and naphthyl under
the standard conditions starting from the substituted E-diol
(5b−d).
To establish the proposed mechanism, intermediate A was
isolated from the known procedure and exposed to standard
reaction conditions that rendered 5t in 59% yield.19
Quinoline and substituted quinoline, including bromo and
alkyne groups on the backbone were tolerated to access to C-3
functionalized pyrroles in high yield (5e−h).
In conclusion, we demonstrated straightforward iron-
catalyzed substituted pyrrole synthesis starting from cis/trans-
buten-1,4-diol and their derivatives via a hydrogen autotransfer
process. The wide scope of amine and alcohol implies that the
reaction was indeed selective and tolerates a variety of
functional groups. 1,4-Hydride addition of α,β-unsaturated
imine is not possible with our presented iron catalyst, even with
external hydrogen pressure.14 Hence, we ruled out the
possibility of an isomerization pathway, although it was
proposed with ruthenium earlier. With the advent of this new
protocol, more sustainable applications will be envisioned for
pyrrole derivatives, especially via further C−H bond function-
More pleasingly, C-2 substituted pyrroles were prepared
using our established protocol in moderate to good yield (5i−
m), which are difficult to dehydrogenate, as iron-catalyzed
reactions using an iron−carbonyl complex are not well-
established for amination of secondary alcohols. Further, to
our delight, 2,4-disubstituted pyrroles were obtained in decent
yield under optimized reaction conditions (5n and o). Then,
we examined reactivity of butyn-1,4-diol with our established
protocol to synthesize pyrrole similar to the previous report by
Watanabe and Williams using ruthenium catalysts. Analogous
C
DOI: 10.1021/acs.orglett.6b02819
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02819.
Experimental methods, optimization of reaction con-
ditions, and other supplementary data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: basker@iitk.ac.in
Notes
(9) Michlik, S.; Kempe, R. Nat. Chem. 2013, 5, 140−144.
(10) Srimani, D.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed.
2013, 52, 4012−4015.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(11) (a) Zhang, M.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2013, 52, 597−601. (b) Zhang, M.; Fang, X.; Neumann, H.; Beller, M.
J. Am. Chem. Soc. 2013, 135, 11384−11388.
■
Financial support was provided by DAE-BRNS (BRNS/CHM/
2014110) through the young scientist award to B.S., which is
gratefully acknowledged. B.E. and M.S. thank IITK and CSIR
for their fellowship. B.E. thanks Sayan Ghosh (affliated with
IISER, Kolkata) for his help during the purification of some
diols.
(12) Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Nat. Chem. 2015, 8, 63−
68.
(13) (a) Kalsi, D.; Laskar, R. A.; Barsu, N.; Premkumar, J. R.;
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ACS Catal. 2016, 6, 2792−2796. (c) Barsu, N.; Rahman, M. A.; Sen,
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