Direct catalytic synthesis of β-(C3)-substituted pyrroles: A complementary addition to the Paal-Knorr reaction

Article abstract of DOI:10.1039/d0cc06357f

The synthesis of β-(C3)-functionalized pyrroles is a challenging task and requires a multistep protocol. An operationally simple direct catalytic synthesis of β-substituted pyrroles has been developed. This one-pot multicomponent method combined aqueous succinaldehyde as 1,4-dicarbonyl, primary amines, and isatins to access hydroxyl-oxindole β-tethered pyrroles. Direct synthesis of the β-substituted free NH-pyrrole is the central intensity of this work. DFT-calculations and preliminary mechanism investigation support the possible reaction pathway. This journal is

Full text of DOI:10.1039/d0cc06357f

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Direct Catalytic Synthesis of β-(C3)-Substituted Pyrroles: A
Complementary Addition to the Paal-Knorr Reaction†
a
a
a
b
c
Amol Prakash Pawar, Jyothi Yadav, Nisar Ahmad Mir, Eldhose Iype, Krishnan Rangan, Sumati
Received 00th January 20xx,
Accepted 00th January 20xx
d
d
a
Anthal, Rajni Kant, Indresh Kumar*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The synthesis of β-(C3)-functionalized pyrroles is a challenging task functionalized pyrrole directly from readily available materials,
and requires a multistep protocol to achieve. An operationally without attachment and removal of the directing group, is
simple direct catalytic synthesis of β-substituted pyrroles has been highly desired.
1
6
developed. This one-pot multicomponent method combined For many reasons, Paal–Knorr reaction is still the most
aqueous succinaldehyde as 1,4-dicarbonyl, primary amines, and convenient way to access pyrroles, and an asymmetric version
isatins to access hydroxyl-oxindole β-tethered pyrroles. Direct of this reaction was recently developed by Tan and co-
17
synthesis of the β-substituted free NH-pyrrole is the central workers. Notably, access to β-substituted pyrrole required
intensity of this work. DFT-calculations and preliminary mechanism elaborately designed 1,4-dicarbonyls as starting material that
investigation support the possible reaction pathway.
may not be easily accessible depending on the nature of the
substituent. We envisioned that the β-functionalized pyrrole,
even a more challenging free NH-pyrrole, could be accessed
directly through a slight variation in this reaction. The successful
development of this hypothesis relies on the utilization of
1
Pyrrole is a basic unit in numerous natural products,
2
3
pharmaceutical, and functional materials. Consequently, the
synthesis of functionalized pyrrole is of continued interest that
4
includes metal-catalyzed reactions, multicomponent reactions,
and classical techniques. Due to mitigated nucleophilicity, the
5
6
C3-position is usually considered as a non-reactive site in
conventional pyrrole chemistry (Scheme 1a). Notably, the
selective access to β-(C3)-substituted pyrrole is often
challenging to realize. The interest in the β-functionalized
pyrroles not only steams from their embedding in several
7
8
natural products, functional materials, but also serve as
9
suitable precursors to access other bioactive compounds. Few
10
specific strategies are known to access this unit that mainly
relied on the prior functionalization of pyrrole, either with the
11
12
electron-withdrawing or sterically bulky groups to adjust
incoming electrophile (Scheme 1b). Additional approaches have
been developed to access β-functionalized pyrrole that includes
metal-catalyzed C-H functionalization, β-alkylation using N-
alkyl pyrroles, and others. Despite significant synthetic
1
3
1
4
15
efforts, the development of a general protocol to access β-
a. Department of Chemistry, Birla Institute of Technology and Science, Pilani
(
Rajasthan) India
E-mail: indresh.chemistry@gmail.com, indresh.kumar@pilani.bits-pilani.ac.in
Department of Chemical Engineering, BITS Pilani, Dubai Campus, Dubai, UAE
Department of Chemistry, BITS Pilani, Hyderabad Campus, Secunderabad, India
X-ray Crystallography Laboratory, Post-Graduate Department of Physics &
b.
c.
d.
Electronics, University of Jammu, Jammu, India
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. (a) Background, (b) Earlier work to access β-substituted pyrrole, (c)
Direct access to β-(C3)-functionalized pyrroles.
†
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J. Name., 2013, 00, 1-3 | 1
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Table 1. Optimization of reaction conditionsa
Table 2. Reaction scope with primary amines 2 and substituted isatins 3.a
View Article Online
DOI: 10.1039/D0CC06357F
aUnless otherwise indicated, the reaction was carried out with succinaldehyde 1
(
(
3.0 M sol, 0.6 mmol), p-anisidine 2a (0.3 mmol), Isatin 3a (0.3 mmol), Catalyst
10 mol%), Solvent (3.0 mL), rt. bIsolated yield of 4aa refers to 3a (≤10% of Paal-
Knorr reaction N-PMP-pyrrole 5 was also obtained).
intermediate enamine-A, in situ generated through the
condensation of succinaldehyde with an amine, with a suitable
electrophile for the α-substitution,18 prior to Paal-Knorr
reaction, to furnish β-functionalized pyrrole (Scheme 1c). Our
19
previous efforts to functionalized pyrroles
using 1,4-
dicarbonyls encouraged us to explore this idea. Herein, we
report a general and direct multicomponent synthesis of
substituted β-(C3)-oxindole-tethered pyrrole under mild
reaction conditions.
Based on our hypothesis, we commenced the multicomponent
investigation using aqueous succinaldehyde 1, p-anisidine 2a,
and isatin 3a as a suitable electrophile (Table 1). An initial
attempt using TFA (10 mol%) in DMSO at room temperature
delivered the desired product 4aa with low yield (entry 1, Table
1
). An improvement in the reaction yield (41%, entry 2, Table 1)
and (67%, entry 3, Table 1) was observed using catalytic Bi(OTf)
and Yb(OTf) in DMSO, respectively. Next, varying the solvents
like DMF and CH CN failed to improve the reaction yields
entries 4-5, Table 1). Pleasingly, compound 4aa was obtained
with 80% yield in EtOH using Yb(OTf) (10 mol%) (entry 6, Table
3
3
3
(
3
aUnless otherwise indicated, reaction was carried out with succinaldehyde 1 (3.0
1
). No desired product was observed in the absence of catalyst M sol, 0.6 mmol), aryl/alkyl amine (0.3 mmol)/NH
4
OAc 2 (0.6 mmol), isatin 3 (0.3
(10 mol%), EtOH (3.0 mL), rt, 2-12 h. Isolated yields of 4 refer
b
mmol), Yb(OTf)
3
(
entry 7, Table 1). Other Lewis acid and solvents lead to poor
c
to 3. Keto-esters (0.3 mmol) were used instead of isatin. (PMP = 4-OMeC
H )
6 4
results (for full screening of Lewis acids & solvents; see Table S1,
ESI†). Collectively, the best result concerning the reaction yield
was obtained in entry 6 (Table 1).
With the optimal conditions in hand, we examine the scope of
the reaction with various amines, isatins (Table 2). A broad
range of electronically differentiated isatins 3a-3o was used for
reaction with aqueous succinaldehyde 1, and p-anisidine 2a to
(
4ha
tert-butyl amine (2j) furnished products 4ja (90% yield), 4jm
91% yield); while biorelevant alkylamines (2n and 2o) and
unprotected polar functional amine (2q) gave related products
ne 4nl 4pl, and 4ql, respectively, in high yields. Notably,
-4ql, Table 2) in excellent yields (up to 91%). Sterically bulky
(
4
,
,
isatins protected with electron-withdrawing groups, such as Ts,
Cbz, Bz, failed to give the expected product, and corresponding
imines condensed with primary amine were obtained, probably
due to the high reactivity of isatin. The single-crystal X-ray
analysis further confirmed the structure of 4ae and 4ja. Next,
we get excited to explore the direct synthesis of the C3-
furnish corresponding C3-pyrroles (4aa-4ao, 70-83% yields).
Suitably substituted as well as alkyl-protected (Me, allyl, benzyl)
isatins were well tolerated and potentially allowing for further
functionalizations. Besides, other aromatic amines were
20
employed successfully to furnished similar products 4ba-4fa
and 4gl in good yields. Next, various alkylamines were examined
with varying isatins; and interestingly, alkylamines emerged as
a better substrate than aryl-amines and took less time for
reaction completion. A wide range of alkyl-amines was
successfully applied to furnished the corresponding pyrroles
4
substituted free-NH-pyrrole. For this purpose, NH OAc was
selected as an amine source under optimized conditions, after
examining other amine sources separately (see Table S2, ESI†).
Excitingly, succinaldehyde
1
, NH
4
OAc 2r, and variously
substituted isatin
3, furnished the corresponding free
2
| J. Name., 2012, 00, 1-3
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DFT-calculations were performed (B3LYP/def2-TZVP) to gain
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DOI: 10.1039/D0CC06357F
more mechanistic insight for reaction outcome (for detailed
optimized structures, see ESI†). The reactivity of pyrrole
in situ generated enamine- was examined with activated
isatin-TiCl complex (Scheme 2). The HOMO of enamine-
5.5 eV) was found higher by 0.4 eV than the HOMO of pyrrole
5.9 eV), thus displaying enhanced nucleophilicity. Similarly,
the LUMO of isatin-complex- 4.02 eV) was found to be
lowered by 1.22 eV, compared to LUMO ( 2.8 eV) of isatin
resulting in a greater electrophilicity. Thus, a superior
interaction is expected between enamine- and isatin-complex-
with an energy gap of 1.48 eV (Scheme 3a). Next, the reactions
of complex- with enamine- and pyrrole were examined by
keeping the Gibbs free energy (G) for reacting species at 0.0
5, and
A
4
B
A
(
−
5 (−
B (−
−
−
3,
A
B
B
A
5
kcal/mol (Scheme 3b). Enamine-
A
reacts with complex-
B
4
via TS-
(∆G =
‡
1
(∆G = 11.01 kcal/mol) to furnished β-(C3)-pyrrole
−
14.0 kcal/mol) after cyclization, while the Friedel-Crafts
‡
reaction of pyrrole
kcal/mol) gave α-(C2)-pyrrole-
more favourable nature of path-I was attributed to the lower
energy barrier of TS- over TS- as well as a higher stability of
over . A separate set of DFT-calculations were performed with
Yb(OTf) at PW91/ZORA-def2-SVP level (see ESI). Next, model
5
with complex-
B
via TS-
2
(∆G = 18.33
6
(∆G =
−
2.1 kcal/mol). Thus, a
1
2
4
6
3
reactions between isatin 3e and pyrroles were performed to
find more information about the reaction pathway.
Interestingly, no reaction was observed between 3e and pyrrole
5
under optimized conditions (Scheme 2c(i)), while bis-pyrrole-
indolin-2-one was obtained by a reaction between 3a and
pyrrole under acidic conditions (Scheme 2c(ii)). Thus, DFT-
8
7
calculations and controlled experiments validate the
involvement of enamine-intermediate in the reaction path.
Based on theoretical study, controlled experiments, and in situ
HRMS study (see Scheme S1, ESI†), a detailed mechanism has
been proposed for this transformation (see Scheme S2, ESI†).
The synthetic utility of the developed protocol was shown at the
gram-scale to access 4ja (1.69 g, 92% yield), and 4qa (1.30 g,
8
9% yield) by simple filtration (>95% purity by HPLC). Next, the
acid-catalyzed Friedel-Crafts reaction of compounds 4ae and
ja with p-cresol and phenol 11, respectively, furnished the
corresponding all-carbon quaternary-center oxindoles 10 (85%)
4
9
Scheme 2. (a) The HOMO & LUMO of pyrrole 5, enamine A, isatin 3 and isatin-
TiCl complex B. (b) Transition State Geometries and Relative Activation Energies
4
for the two possible ways of reacting partners. Path-I: access to C-3 substituted (Scheme 2d(i)) and 12 (92%) (Scheme 2d(ii)).
pyrrole via reaction of enamine-A with complex-B (TS-1), Path-II: access to C2-
substituted pyrrole via Friedel-Crafts reaction of pyrrole 5 with complex-B (TS-2).
‡
Gibbs activation energies (∆G , kcal/mol) and Gibbs reaction energies (∆G,
kcal/mol) are shown. (c) Model reactions between isatin 3e and preformed
pyrroles 5 and 7. (d) Synthesis of quaternary substituted oxindoles 10 and 12.
Conclusions
In summary, the first direct catalytic synthesis of β-
functionalized pyrroles has been developed. This
multicomponent protocol highlights the simplicity of stitching
together aqueous succinaldehyde, primary amines, and isatins
to access β-(C3)-oxindole-tethered pyrroles under mild
NH-pyrroles 4ra
-4rd, 4rp, 4re, 4rh, and 4rl in good yields (up to
7
5%). The single-crystal X-ray analysis confirmed the structure
2
0
of compound 4rl
.
These preliminary results for the direct
conditions.
experimental outcome. The synthetic applicability was shown
i) for the gram-scale synthesis, and (ii) synthesis of quaternary-
DFT-calculations
further
supported
the
access to β-functionalized free NH-pyrrole are novel and offer
an opportunity to stitch other functionality at this position.
Besides, methyl pyruvate 3q and correspnding trifluoro-
compound 3r, were also examined as a suitable electrophile
with aryl/alkyl-amine, and furnished corresponding β-
substituted pyrroles 4aq (68%), 4oq (68%), and 4ar (72%) under
optimized conditions (Table 2).
(
center oxindoles. This method represents a valuable resource
to secure other electrophiles at the β-position of pyrrole
asymmetrically, particularly for free NH-pyrrole. Efforts in this
direction are currently underway in our laboratory.
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Tarui, T. Hamada, T. Takagi, T. Takeuchi, M. KaVjieinwoA,rtiJc.leMOnelinde.
Conflicts of interest
There are no conflicts to declare.
Chem., 2012, 55, 4446.
DOI: 10.1039/D0CC06357F
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Acknowledgements
This work was financially supported by DST-SERB
(
CRG/2020/003424). AP and JY thank BITS Pilani for Research
Fellowships. The authors thank DST-FIST (SR/FST/CSI-270/2015)
for HRMS facility to the Department of Chemistry.
1
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M. Bultman, K. Chen, S. Ivy, R. L. Schild, J. C. Tripp, S.
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Eastgate, D. A. Conlon, Org. Process Res. Dev., 2017, 21, 1122;
1
0 The X-ray crystallographic structures for 4ae (CCDC NO.
1
1
825913), 4ja (CCDC NO. 1973218), and 4rl (CCDC NO.
(
e) Y. Arikawa, H. Nishida, O. Kurasawa, A. Hasuoka, K. Hirase,
973219) have been deposited at the Cambridge Crystallogr-
N. Inatomi, Y. Hori, J. Matsukawa, A. Imanishi, M. Kondo, N.
aphic Data Centre (CCDC) (for more details see ESI†).
4
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC06357F
Graphical Abstract
O
O
Yb(OTf) (10 mol%)
3
CHO
N
EtOH, rt
NH2 +
HO
N
+
O
48 examples
CHO
N
C3
up to 92% yields
open-flask multicomponent reaction
= Ar/alkyl/H
catalytic and oprationally simple protocol
gram-scale synthesis and DFT-calculations
A Lewis-acid catalyzed direct multicomponent synthesis of β-(C3)-substituted pyrroles is
developed in good to high yields, using aqueous succinaldehyde, primary amines, and isatins under
mild conditions. Direct access to the β-substituted free NH-pyrrole is the main strength of the work
along with DFT-calculations.