One-Pot Synthesis of 3-Substituted 2-Arylpyrrole in Aqueous Media via Addition-Annulation of Arylboronic Acid and Substituted Aliphatic Nitriles

Article abstract of DOI:10.1021/acs.orglett.7b00490

Pd(II)-catalyzed C-C coupling reactions between substituted aliphatic nitriles and arylboronic acids followed by in situ cyclodehydration have been employed for the first time to synthesize a wide variety of 3-substituted 2-aryl-1H-pyrroles in aqueous acetic acid. This one-pot synthesis is green, and it conforms to atom economy. The structures of two representative pyrroles, 3k and 5f, were confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1021/acs.orglett.7b00490

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of 3‑Substituted 2‑Arylpyrrole in Aqueous Media
via Addition−Annulation of Arylboronic Acid and Substituted
Aliphatic Nitriles
Md Yousuf and Susanta Adhikari*
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India
S
* Supporting Information
ABSTRACT: Pd(II)-catalyzed C−C coupling reactions between
substituted aliphatic nitriles and arylboronic acids followed by in
situ cyclodehydration have been employed for the first time to
synthesize a wide variety of 3-substituted 2-aryl-1H-pyrroles in
aqueous acetic acid. This one-pot synthesis is green, and it
conforms to atom economy. The structures of two representative
pyrroles, 3k and 5f, were confirmed by X-ray crystallographic
analysis.
yrrole is a basic structural motif of numerous important
leading to α-arylation products.10 In our previous studies, we
Pbiologically active natural products, pharmaceuticals, have shown that ethyl cyanoacetate and substituted ethyl
agrochemicals, and functional materials.1 Highly functionalized
cyanoacetate are useful acyl equivalents for the synthesis of
alkyl aryl ketones.11 In light of this fact, we envisaged that
pyrroles are the subunits of heme, chlorophyll, bile pigments,
substitution of one of the active methylene protons of ethyl
cyanoacetate/malononitrile by an alkyl group bearing a pendent
aldehyde function should serve as an ideal substrate for pyrrole
synthesis. Nucleophilic addition of an arylboronic acid to the
nitrile using a mild acid, such as aqueous acetic acid, should
lead to a Paal−Knorr intermediate (intermediate E in Scheme
3). This 1,4-imino aldehyde might then spontaneously undergo
intramolecular annulation in situ, and dehydration would afford
3-substituted 2-arylpyrroles in a single flask. Accordingly, we
selected ethyl 2-cyano-4,4-diethoxybutanoate (2) as an electro-
philic partner for the Pd(II)-catalyzed nucleophilic addition of
various commercially available arylboronic acids using ubiq-
uitous bipyridyl ligand (bpy). Gratifyingly, 3-carbethoxy-2-
arylpyrrole was obtained by simply heating the reaction at 80
°C in the presence of aqueous acetic acid. This convenient one-
pot synthesis of pyrrole appears to involve both the addition of
an aryl group of arylboronic acid to substituted nitriles followed
by an amination−annulation−dehydration sequence in the
same reaction system.
Initial investigations comprised phenylboronic acid (1a) and
ethyl 2-cyano-4,4-diethoxybutanoate (2) as reaction partners to
establish the optimal reaction condition (Table 1). Following
our earlier protocol of addition of aryboronic acids to
substituted ethyl cyanoacetate,11 a test reaction with phenyl-
boronic acid (1a), ethyl 2-cyano-4,4-diethoxybutanoate (2),
Pd(OAc)2, and ligand in the presence of excess triflic acid
(TfOH) in water medium was performed under air (Table 1,
entry 1). Unfortunately, the reaction mixture immediately
turned black without any characteristic product formation;
and vitamin B12. In particular, the 2-arylpyrrole core is present
in various fluorescent dyes, pharmaceutical intermediates, and
pesticide precursors.2 These classes of molecules are widely
used in C−H activation where the pyrrole ring serves as a
directing group for ortho-palladation of the benzene ring for the
synthesis of complex natural products.3 Hence, there is a
sustained interest in developing improved methods for the
synthesis of this class of compounds. In recent years, synthesis
of 2-arylpyrroles has been accomplished by cycloaddition,4
transition-metal-mediated cyclization,5 or multicomponent
reactions.6 However, they rely on elaborately designed
substrates which are either not easily accessible or not stable
enough to be stored for a long time. Palladium-mediated cross-
coupling chemistry7 for this purpose requires regioselective
halogenations on the pyrrole core, suitable N-protecting
groups, etc.
Although synthesis of 3-substituted 2-arylpyrroles is known
in the literature,8 the scope of such synthetic methods is rather
limited.8 Nevertheless, the success of the reaction solely relies
on the choice of suitable organic solvent and the use of
ammonium acetate as an amine source.8a We therefore
developed a versatile and convenient one-pot procedure that
allowed easy construction of 3-substituted 2-arylpyrroles via
nucleophilic addition of arylboronic acids to aliphatic nitriles
followed by cyclodehydration, a strategy being reported for the
first time. This reaction is atom-economical and involves green
chemistry. The preliminary results are disclosed in this paper.
The addition reaction of aliphatic nitrile using arylboronic
acid is usually difficult and less common.9 The nitrile group is
not activated enough to readily undergo nucleophilic addition
reaction, and nitrile-containing active methylene compounds
tend to be deprotonated in the presence of palladium catalysts
Received: March 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00490
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Organic Letters
Letter
a
Table 1. Optimization Studies
b
entry
Pd source
additive
solvent
time (h)
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
−
TfOH/H2O (0.2 mL/0.4 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.2 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
dioxane/H2O (0.4 mL/0.2 mL)
H2O/AcOH (0.4 mL/0.2 mL)
H2O/AcOH (0.3 mL/0.3 mL)
DMF/H2O (0.4 mL/0.2 mL)
DMSO/H2O (0.4 mL/0.2 mL)
DME/H2O (0.4 mL/0.2 mL)
THF/H2O (0.4 mL/0.2 mL)
toluene/H2O (0.4 mL/0.2 mL)
PEG-600/H2O (0.4 mL/0.2 mL)
H2O/AcOH (0.3 mL/0.3 mL)
H2O/AcOH (0.4 mL/0.2 mL)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
0
30
0
2
TfOH
TfOH
TfOH
TfOH
AcOH
Sc(OTf)3
AgTFA
AgOTf
Cu(OTf)2
Zn(OTf)2
Sn(OTf)2
SnCl4
FeCl3
TiCl4
3
4
trace
27
40
62
trace
10
trace
trace
0
5
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
5
0
10
10
5
TFA
PTSA
−
−
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
−
70
81
0
0
5
5
10
10
77
0
c
26
d
27
AcOH
a
Reaction conditions: PhB(OH)2 (0.6 mmol), ethyl 2-cyano-4, 4-diethoxybutanoate (0.5 mmol), additive (0.5 mmol), Pd(OAc)2 (5 mol %), bpy
b
c
d
(2,2′-bipyridine) (5 mol %), under air. Isolated yield. 2-(2,2-Diethoxyethyl)malononitrile used as an electrophile. No ligand used.
perhaps strongly acidic conditions led to polymerization of
pyrrole. When we set up the same reaction with an equivalent
amount of TfOH instead of an excess in 2:1 dioxane−water, we
isolated 3-carbethoxy-2-phenylpyrrole, albeit in low yield. We
then investigated different palladium salts with an equivalent of
TfOH (Table 1, entries 2−5) to increase the yield. Among the
palladium sources used, Pd(OAc)2 exhibited the highest
catalytic reactivity with 30% yield (Table 1, entry 2).
Subsequently, various Lewis acid additives were also screened
to optimize the yield. It was found that the use of 1 equiv of
acetic acid or Sc(OTf)3 is essential (Table 1, entries 6 and 7)
for achieving a moderate yield of the desired product. Use of
other additives, such as AgTFA, AgOTf, Cu(OTf)2, Zn(OTf)2,
Sn(OTf)2, SnCl4, FeCl3, TiCl4, CF3CO2H (TFA), and p-
toluenesulfonic acid (pTSA), were not useful (Table 1, entries
8−17). We next examined the solvent effect and found that
water was superior to DMF, DMSO, DME, THF, toluene, and
PEG-600 (Table 1, entries 20−25). We were pleased to
discover that when the reaction was performed in H2O/HOAc
(1:1) mixture as a solvent system, the yield dramatically
increased to 81% (Table 1, entry 18 vs 19). It is noteworthy
that these optimized conditions gave comparable results also
with another substituted nitrile, i.e., 2-(2,2-diethoxyethyl)-
malononitrile in 2 h (Table 1, entry 26). The reaction did not
proceed in the absence of ligand and turned black immediately
(Table 1, entry 27). Significantly, this one-pot addition−
annulation sequence proved optimal and efficient for the
construction of a wide variety of 2-arylpyrrole cores with 3-
carbethoxy/nitrile substituents (vide infra).
To examine the generality of this strategy, a large number of
electronically and structurally diverse arylboronic acids and
ethyl 2-cyano-4,4-diethoxybutanoate (2) were exposed to these
reaction conditions, and in most of the cases 3-carbethoxy 2-
arylpyrrole products, 3a−n, were obtained in moderate to very
good yields. Results are summarized in Scheme 1. Arylboronic
acids containing electron-donating groups provided excellent
yields (3b, 3c, 3f, 3g, and 3k; Scheme 1). A lack of reactivity in
the case of electron-withdrawing substituents on the arylbor-
onic acid can be compensated by increasing the temperature
(3d,e,h−j, Scheme 1). This perhaps is due to the lower
nucleophilicity of the aryl group of arylboronic acid, which
slows the transmetalation step to the cationic Pd(II) complex
(vide infra, Scheme 3).13
Sterically hindered arylboronic acids also afforded products
in good to excellent yields (3b,m,n, Scheme 1). Despite heating
in an acidic medium, it is remarkable that the desired pyrroles
were obtained from −OMe, and −X (F, Cl, Br) substituted
arylboronic acids in high yields (3g,k,d,h−j). This offers a clear
opportunity for these substrates to be used for further
transformations. To expand the structural diversity, we installed
another heterocyclic scaffold, a thiophene moiety, at the 2-
B
DOI: 10.1021/acs.orglett.7b00490
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Organic Letters
Letter
Scheme 1. Scope of Arylboronic Acids in Substituted Ethyl
Cyanoacetate
Scheme 2. Scope of Arylboronic Acids in Substituted
Malononitrile
a
Reaction conditions: ArB(OH)2 (1.2 mmol), 2-(2,2-diethoxyethyl)-
malononitrile (1 mmol), H2O/AcOH (0.6 mL/0.6 mL), Pd(OAc)2 (5
b
mol %), L (5 mol %), under air. Isolated yield.
Figure 1. X-ray crystal structures of 3k and 5f (capped sticks
representation).
a
Reaction conditions: ArB(OH)2 (1.2 mmol), ethyl 2-cyano-4, 4-
reaction as shown in Scheme 3. First, transmetalation of
arylboronic acid by Pd(II) catalyst (A)13 generates arylpalla-
dium species B. Then the nitrile group coordinates to the
diethoxybutanoate (1 mmol), H2O/AcOH (0.6 mL/0.6 mL),
Pd(OAc)2 (5 mol %), L (5 mol %), under air, 80 °C. Isolated
yield. At 90 °C.
b
c
Scheme 3. Proposed Mechanistic Cycle
position of the pyrrole nucleus (3l) in good yield by employing
3-thienylboronic acid.
Encouraged by the above results, we turned our attention to
another substituted aliphatic nitrile such as malononitrile to
make 3-cyano-substituted 2-arylpyrroles. Nitriles are resource-
ful synthetic scaffolds for elaboration into a diverse array of
building blocks such as aldehydes, ketones, amides, carboxylic
acids, and amines.12 When 2-(2,2-diethoxyethyl)malononitrile
(4) was used as an electrophilic partner for arylboronic acid,
successful installation of a nitrile at the 3-position of the pyrrole
core was achieved (5a−f) as shown in Scheme 2.
Finally, we confirmed the structure of 3-carbethoxy- and 3-
cyano-substituted 2-arylpyrrole derivatives by a single-crystal X-
ray diffraction study of two such representative compounds 3k
(CCDC 1527805) and 5f (CCDC 1527806) as displayed in
Figure 1.
In line with our earlier observation,11 we can speculate a
plausible mechanism for the aqueous acid mediated domino
C
DOI: 10.1021/acs.orglett.7b00490
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00490.
Experimental procedures, analytical data for all new
compounds, and NMR spectra (PDF)
X-ray data for 3k (CIF)
(8) (a) Wiest, J. M.; Bach, T. J. Org. Chem. 2016, 81, 6149−6156.
(b) Padwa, A.; Smolanoff, J.; Tremper, A. J. Am. Chem. Soc. 1975, 97,
4682−4691. (c) Benages, I. A.; Albonico, S. M. J. Org. Chem. 1978, 43,
X-ray data for 5f (CIF)
AUTHOR INFORMATION
4273−4276. (d) Alberola, A.; Gonzal
́ ́
ez Ortega, A.; Sadaba, M. L.;
■
Sanudo, C. Tetrahedron 1999, 55, 6555−6566.
̃
Corresponding Author
*E-mail: adhikarisusanta@yahoo.com.
ORCID
(9) (a) Wang, X.; Wang, X.; Liu, M.; Ding, J.; Chen, J.; Wu, H.
Synthesis 2013, 45, 2241−2245. (b) Zhao, B.; Lu, X. Org. Lett. 2006, 8,
5987−5990. (c) Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding,
J.; Wu, H. J. Org. Chem. 2013, 78, 5273−5281.
Susanta Adhikari: 0000-0002-5204-3876
Notes
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Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
4641−4642. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234−245.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) Yousuf, M.; Das, T.; Adhikari, S. New J. Chem. 2015, 39, 8763−
8770.
M.Y. acknowledges CSIR, India, for a research fellowship. S.A.
acknowledges the Science and Engineering Research Board
(Project No. SR/S1/OC-101/2012) for financial support.
(12) Fatiadi, A. J. In Preparation and Synthetic Applications of Cyano
Compounds; Patai, S., Rappaport, Z., Eds.; Wiley: New York, 1983.
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DOI: 10.1021/acs.orglett.7b00490
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