Synthesis of Polyfunctionalized Pyrroles via a Tandem Reaction of Michael Addition and Intramolecular Cyanide-Mediated Nitrile-to-Nitrile Condensation

Article abstract of DOI:10.1021/acs.joc.8b00465

A new approach for the synthesis of tetrasubstituted/functionalized NH-pyrroles from gem-diactivated acrylonitriles and TMSCN has been developed. The strategy utilizes the generation of vic-dinitrile via Michael addition and cyanide-mediated nitrile-to-nitrile cyclocondensation, which proceed in tandem guided by manifold roles of CN . An extended application to the production of fused pyrrole has also been realized.

Full text of DOI:10.1021/acs.joc.8b00465

Subscriber access provided by UNIV OF DURHAM
Synthesis of polyfunctionalized pyrroles via a tandem reaction of Michael
addition and intramolecular cyanide-mediated nitrile-to-nitrile condensation
Sankar K. Guchhait, Shailendra Sisodiya, Meenu Saini, Yesha V. Shah,
Gulshan Kumar, Divine P Daniel, Neha Hura, and Vikas Chaudhary
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Apr 2018
Downloaded from http://pubs.acs.org on April 19, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of polyfunctionalized pyrroles via a tandem reaction of Michael
addition and intramolecular cyanide-mediated nitrile-to-nitrile
condensation
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sankar K. Guchhait,* Shailendra Sisodiya§, Meenu Saini§, Yesha V. Shah, Gulshan Kumar, Divine P Daniel, Neha Hura
and Vikas Chaudhary
Department of Medicinal Chemistry, National Institute of Pharmaceutical and Education Research (NIPER), Sector
67, SAS Nagar (Mohali), Punjab 160062, India.
Email: skguchhait@niper.ac.in
A new approach for synthesis of tetra-substituted/functionalized NH-pyrroles from gem-diactivated acrylonitriles
and TMSCN has been developed. The strategy utilizes generation of vic-dinitrile via Michael addition and cyanide-
mediated nitrile-to-nitrile cyclocondensation, which undergo in tandem guided by manifold roles of “CN”. An
extended application to production of fused-pyrrole has also been realized.
Pyrrole-class of compounds possess diverse biological and pharmaceutical properties.1,2 Several drugs
(e.g., Lipitor, Tolmetin, Ketorolac, Sunitinib, Pyrivinium) contain pyrrole core. In this family, 2-
aminopyrrole is a privileged medicinal template. Compounds containing this scaffold exhibit versatile
biological activities.3 The motif is also present in several natural products, e.g., Rigidins, Storniamide A,
Lamellarin O, and biologically active compounds.3,4 In addition, reactivity of 2-aminopyrrole as an
amidine functional motif is frequently applied to synthesis of various pyrrole-fused heterocycles.5,6,7
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 28
1
2
3
4
5
Conventional methods for synthesis of pyrroles are the Piloty-Robinson,8 Knorr,9 Paal−Knorr,10
and Hantzsch11 reactions. Significant development has been made in exploring different routes for
6
7
8
construction of pyrrole skeleton.12 For synthesis of
N-substituted 2-aminopyrroles, various
9
methods13 including metal-catalyzed (Au, Au/Zn, Pd)14 and isocyanide based reactions15 have
been reported. However, the synthesis of 2-aminopyrrole skeleton that possesses unsubstituted 2-
amine as well as ring NH is rare.16 On the other hand, these functionalities are important for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
further structural tune of compounds. 2-Amino-3H-pyrrole scaffold was prepared via a reaction of
ketone and thiol with malononitrile as a source for dual role of ‘CN’.17 Obviously, a new direct
approach for preparation of poly-substituted/functionalized 2-amino-NH-pyrrole core remains
valuable.
The intramolecular cyclization via condensation of functional groups plays an excellent role in
organic synthesis. For example, there are several popular conventional reactions for dicarbonyl-
containing compounds. The important examples are cyclization of 1,4-dicarbonyl to form furan
(Paal-Knorr),10 reductive coupling to form alkene (McMurry),18 pinacol coupling,19 and acyloin20
or benzoin condensation.21 An intramolecular cyclization via [4+2]-cycloaddition based nitrile
oxide dimerization to construct carbocyclic structure has been reported.22
Herein, we report a new approach for synthesis of 2-aminopyrroles via a strategic tandem process
of the Michael addition to form vic-dinitrile and its intramolecular cyclization by a cyanide-
mediated nitrile-to-nitrile condensation. The reaction constructs multiple C–C/N bonds and
involves manifold C/N-nucleo- and electrophilic roles of nitrile. The compounds obtained are
uniquely decorated with poly-substitutions/functionalities (amidine and 1,2-bis-nitrile). It is worth
to mention that numerous drugs possess aromatic nitrile23 and heterocyclic amidine that provides
an interesting pattern of H-bond donor and acceptor interactions with enzyme or receptor and
favourable physicochemical properties.24
ACS Paragon Plus Environment

Page 3 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
We initiated investigation for a reaction of 2-(4-methoxybenzylidene)malononitrile with
TMSCN.25 Si-hypercoordination of TMSCN with a Lewis base generates a silicate intermediate
that bears potential of releasing active cyanide nucleophile.26 With this in mind, several organic
and inorganic bases and other suitable agents as nucleophilic promoters for desilylation of
TMSCN were evaluated (Table 1). Interestingly, our strategic reaction process provided the
desired product in significant yields. Carbonates as effective promoters were previously
reported.27 In the present reaction, organic bases proved to be superior to inorganic bases
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1: Optimization study
#
Variable
Yield(%)b
Base (2 equiv), Dioxane-H2Oc, 95 °C
#
Variable
Yield(%)b
46
1
2
3
4
5
6
7
Et3N
DIPEA
DMAP
DABCO
DBU
54
55
48
68
90
44
41
8
Cs2CO3
TBAF
KHF2
KF
9
42
10
11
12
13
40
55
45
22
K3PO4
-
Na2CO3
K2CO3
DBU (2 equiv), Solventc (2 mL), 95 °C
14c Dioxane-
H2O
90
20
EtOH
38
15
Dioxane
68
30
21 c
22 c
DMF-H2O
83
88
16
Toluene
MeCN-
H2O
17
18
DMF
58
62
23
H2O
35
85
MeCN
24 c, d
Dioxane-
H2O
Dioxane-
H2O
19
tBuOH
32
25 c,e
65
aSubstrate,
reagents
and
conditions:
2-(4-
methoxybenzylidene)malononitrile 1 (1mmol), TMSCN (2 equiv); byield
c
for maximum conversion in optimum time; organic solvent-H2O (4:1;
1.6 and 0.4 mL) dDBU (1 equiv); eDBU (0.5 equiv).
including carbonates. DBU was found to be most efficient providing product in 90% yield. DBU
also accelerated the reaction rate. The reaction without base provided 20% yield of product. The
efficient role of DBU in the reaction can be attributed to the unique silicon-philicity of its tertiary
amidine-amine motif that possibly promotes effective release of cyanide ion from TMSCN.27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 28
1
2
3
4
5
6
7
8
9
Various solvents were investigated. Dioxane, DMF and MeCN provided higher yields.27 Dioxane-
water was found to be most effective. Water plausibly acts as proton source28 and induces H-
bond-driven activation of functionalities.29 Variation in volumetric ratio of dioxane and water
solvents indicated that dioxane-water (4:1) was best. The use of water as exclusive solvent was
detrimental for the reaction. Although highest yield (90%) was obtained with 2 equiv of DBU, the
reaction with 1 equiv. DBU underwent smoothly without significant loss in yield (85%; entries 14
vs 24). Use of 0.5 equiv. DBU provided 65% yield (entry 25). These indicate a catalytic role of
DBU involved in the present reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We investigated also the efficiency of commonly used several other metal and non-metallic
cyanating agents.23,30 The reactions either did not undergo or were trace-to-moderate yielding;
CuCN (0%), Zn(CN)2 (0%), K4[Fe(CN)6] (trace), pyruvonitrile (50%), benzoyl cyanide (10%),
and ethyl cyanoformate (45%). These imply that TMSCN not only acts as cyanide-source but
also plays additional role in the present reaction. Plausibly, silyl by-product generated from
TMSCN acted as Lewis acid in electrophilic activation of substrate and intermediate.25,26,28 The
use of TMSCN as “CN” group-transfer reagent is well-known in numerous transformations, for
example, cyanosilylation reactions of carbonyl,31 imine (Strecker32 and Reissert reaction),33
aziridine,34 oxirane,35 and nitrone.36 In the present reaction, TMSCN provides eventual multiple
C–C/N bonds construction and produces poly-functionalized pyrroles. X-ray crystallography
confirmed the molecular constitution of the product (See Fig S1, SI) identified by spectroscopies.
We next set out to explore the substrate scope of the developed method towards preparation of
versatile tetrasubstituted 2-amino-NH-pyrroles. Alkylidene malononitrile substrates possessing
various aryls, heteroaryls, alkyls and functionalities underwent the reaction with TMSCN (Table
2). The aryls with different electronic (electron-donating and withdrawing) and steric properties
were compatible, though electron-withdrawing functionalities provided relatively low yields
compared to electron-donating groups.
ACS Paragon Plus Environment

Page 5 of 28
The Journal of Organic Chemistry
1
2
3
Table 2. Substrates scope: Synthesis of tetrasubstituted 2-amino-NH-
pyrrole-nitriles a,b
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aSubstrate, reagents and conditions: gem-diactivated olefin 1(1 mmol),
TMSCN (2 equiv), DBU (2 equiv), 1,4-Dioxane-H2O (4:1; 1.6 and 0.4 mL), 95
ºC, 1-3 h. bIsolated yield for maximum conversion in optimum time.
However, an enhanced conjugated benzylidenemalononitrile, derived from cinnamaldehyde and
malononitrile, produced multiple non-isolable products. We investigated also other gem-
diactivated olefins such as the olefins derived from cyanoacetate (3u-3v). The corresponding 2-
amino-NH-pyrroles were obtained. Interestingly, the pyrrole-producing process occurred
chemoselectively in the presence of ester functionality which is more reactive than nitrile.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Isolation of vic-dinitrile intermediate and its use as substrate in the reaction
Performing the reaction at gram scale (6 mmol) did not cause significant decrease in yield (3a
,
82%) of the product.
We were then interested to identify the possible mechanism. In the course of reaction of substrate
1a, a product was isolated from the mixture obtained at intermediate time and found to be 2-(4-
methoxyphenyl)ethane-1,1,2-tricarbonitrile (intermediate 1ai, Scheme 1, See SI for data). The use
of isolated intermediate (1ai) as substrate in the reaction with TMSCN (1 equiv) under identical
conditions provided similar yield (92%) of the 2-aminopyrrole product 3a. For substrate 1v that
possesses dissimilar functionality, an intermediate product was isolated and found to be vic
-
dinitrile 1vi (Scheme 1). Use of intermediate 1vi as substrate in separate reaction afforded product
3v in similar yield (53%). The reaction of diarylacrylonitrile 1w afforded the intermediates (1wi
meso and dl isomers) (Scheme 1). However, further reaction of intermediates 1wi as substrates
towards formation of product did not undergo plausibly due to significant stability of the
Scheme 2. Plausible mechanism
ACS Paragon Plus Environment

Page 7 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
intermediates. Only interconversion between meso and dl isomers was observed.37 These clearly
indicate that the reaction undergoes via a pathway involving formation of the vic-dinitrile
intermediate. A test by picric acid strip (color changed from yellow to brown) detected the
presence of cyanide anion in the mixture during course of the reaction.38 For the reaction of
substrate 1a to produce 2-aminopyrrole 3a, separate experiments using TMSCN of 1 and 2 equiv.
provided the product in 44% and 90% yields, respectively. This indicates that the reaction
pathway is associated with involvement of 2 equiv. TMSCN. Based on all these results and
incongruent to the literature,26 a plausible mechanism has been proposed (Scheme 2). It involves
DBU-promoted cyano release from TMSCN, Michael addition to acrylonitrile, intramolecular
cyclization via cyanide-mediated condensation of nitriles, and aromatization-driven 1,3-
prototropic shift. High regioselectivity obtained in this protocol can be attributed to relative higher
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
acidity of
α-hydrogen than β-hydrogen, which provides regioselectively ketenimine 1b. An
additional controlled experiment revealed interesting observation. The reaction of Michael adduct
intermediate 1ai with DBU in the absence of TMSCN results in formation of product 2-amino-5-
cyanopyrrole 3a, but in much lowered yield (11%). Interestingly, substrate 1a was also produced
in 10% yield in the reaction. On the other hand, the reaction of the intermediate 1ai in presence of
both DBU and TMSCN (identical conditions to optimized method) produces desired 2-amino-5-
cyanopyrrole 3a in 92% yield, which is similar to yield (90%, Table 2) obtained in optimized
method and, moreover, substrate 1a was not produced. These clearly indicate that an alternate
pathway takes place for the conversion of intermediate 1ai to product 3a in the absence of
TMSCN (See details in SI, Scheme-S1). It is worth to note that the reaction pathway of the
established approach provides a unique feature of incorporating in the product skeleton a ring-
amidine and an aromatic nitrile which is generally accomplished by transition-metal-catalyzed
cyanation.
We investigated also to find further an exemplary extended synthetic utility of our developed
approach. The product 3a in a reaction39 with aldehyde and alkyne produces pyrrole-fused
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 28
1
2
3
4
5
6
7
8
pyrimidine scaffold 4a that contains multiple substitutions/functionalities (Scheme 3).
Remarkably, the synthesis of pyrrole-fused pyrimidines is important. The compounds containing
this skeleton have been found to display various biological activities.40
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Extended application: Synthesis of pyrrole-fused pyrimidine
skeleton
In conclusion, we have discovered the synthesis of tetra-substituted/functionalized 2-amino-NH-
pyrroles via a new reaction of gem-diactivated acrylonitrile with TMSCN. The approach involves
a strategic utilization of Michael addition and an unprecedented cyanide-mediated nitrile-to-nitrile
condensation, which construct amidine and aromatic nitrile in the product skeleton. The
developed protocol is chemoselective, provides moderate to excellent yields of products, and uses
easily accessible starting materials. The pyrrole-products possess multiple functional motifs and
have potential in applications to numerous structural tunes.
EXPERIMENTAL SECTION
General Information: Infrared (IR) spectra were recorded on a Perkin Elmer FTIR with ATR & IR
1
Microscope spectrometer. H NMR spectra were measured on a Bruker Avance III-400 (400 MHz)
spectrometer. Data were reported as follows: chemical shifts in ppm from tetramethylsilane as an internal
standard in CDCl3/CD3OD/DMSO-d6/D2O integration, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet, td = triplet of doublet, dt = doublet of triplet, br = broad), and coupling constants
(Hz). 13C NMR spectra were measured on a Bruker Avance III-400 (100 MHz) spectrometer with
complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent as an
internal standard. High-resolution mass spectra (HRMS) were performed on Bruker maxis Q-TOF. For
thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel
ACS Paragon Plus Environment

Page 9 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
60 GF254, 0.25 mm) were used. The products were purified by column chromatography silica gel 100-
200 (Merck, silica gel 100-200 mesh, neutral, spherical).
7
8
9
All commercially obtained reagents were used as received.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
gem-diactivated olefins were prepared following the literature known methods.41
Representative experimental procedure for synthesis of 2-Amino-3-(4-methoxyphenyl)-1H-pyrrole-
4,5-dicarbonitrile (3a, Table 2): To 2-(4-methoxybenzylidene)malononitrile (1 mmol, 184 mg), taken in
a sealed tube were added solvent Dioxane-H2O (1.6 mL and 0.4 mL, respectively) and DBU (1 mmol, 0.3
mL). The mixture was cooled to 0°C and TMSCN (1 mmol, 0.25 mL) was added. The tube was sealed.
The reaction mixture was then stirred at 95 °C. The progress of the reaction was monitored by TLC. After
completion of the reaction conversion, the resultant mixture was then concentrated by rotary evapourator
under vacuum. The column chromatographic purification of crude mass was performed on silica gel
(mesh 100-200) partially deacidified by passing triethylamine (1-2 mL) using EtOAc-hexane (50%) as
eluting solvent. The product 2-Amino-3-(4-methoxyphenyl)-1H-pyrrole-4,5-dicarbonitrile (3a) was
isolated (214 mg, 90% yield).
Other products (3b-v, Table 2) were also prepared following this representative procedure.
Characterization Data for Intermediates (1ai, 1vi, 1wi, Scheme 1)
2-(4-methoxyphenyl)ethane-1,1,2-tricarbonitrile (1ai, Scheme 1)
1
Off white solid, 89 mg, 42%, m.p. 90-92 °C, H NMR (400 MHz, DMSO-d6): δ 7.46 (d, J = 8.7 Hz, 2H),
7.08 (d, J = 8.7 Hz, 2H), 5.77 (d, J = 6.2 Hz, 1H) 5.46 (d, J = 6.16 Hz, 1H), 3.79 (s, 3H) C{1H}NMR
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 28
1
2
3
4
5
6
7
8
(100 MHz, DMSO-d6): δ 160.3, 129.6, 121.6, 117.0, 114.8, 111.8, 55.3, 36.0, 28.9; IR: υmax 3434, 2943,
2168, 2103, 1650, 1325, 693 cm-1; MS (ESI) m/z: calcd. for C12H9N3ONa [M+Na]+ 238.0, found: 234.0.
(erythro+threo) Ethyl 3-(4-chlorophenyl)-2,3-dicyanopropanoate (1vi, Scheme 1):
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pale yellow liquid, 1H NMR (400 MHz, CDCl3): δ 7.44-7.41 (m, 8H), 4.60 (d, J = 5.1 Hz, 1H), 4.55 (d, J
= 6.4 Hz, 1H), 4.41-4.29 (m, 4H), 4.12 (d, J = 6.4 Hz, 1H), 3.89 (d, J = 5.1 Hz, 1H), 1.36 (t, J = 7.2 Hz,
3H), 1.31 (t, J = 7.2 Hz, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3): δ 162.4, 162.3, 136.4, 136.2, 129.9,
129.8, 129.8, 129.3, 128.9, 128.3, 116.6, 115.9, 112.6, 112.6, 64.4, 64.4, 43.6, 42.9, 37.1, 35.4, 13.9, 13.9
ppm; IR: υmax 3468, 2939, 2252, 1745, 1494, 1016, 835 cm-1; HRMS (ESI) m/z: calcd. for C13H11ClN2O2
Na [M+Na]+ 285.0407, found:285.0398.
2,3-bis(4-Methoxyphenyl)buta-1,3-diene-1,4-diimine (1wi, Scheme 1):
meso form:
1
Peach solid, 175 mg, 60%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 7.30 (d, J = 8.0 Hz, 4H),
13
6.99 (d, J = 8.0 Hz, 4H), 5.01 (s, 2H), 3.77 (s, 6H) ppm; C{1H}NMR (100 MHz, DMSO-d6): δ 160.0,
ACS Paragon Plus Environment

Page 11 of 28
The Journal of Organic Chemistry
1
2
3
4
130.2, 124.6, 119.2, 114.7, 55.6 ppm; IR: υmax 3444, 2996, 2839, 2246, 1614, 1515, 1251, 1178, 1030,
821 cm-1; HRMS (ESI) m/z: calcd. for C18H16N2O2Na [M+Na]+ 315.1110, found: 315.1107.
5
6
7
8
9
dl Isomer:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
White solid, 44 mg, 15%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 8.7 Hz, 4H), 7.30
(d, J = 8.6 Hz, 4H), 6.99 (d, J = 4.2 Hz, 8H), 6.97 (s, 4H), 5.01 (s, 2H), 5.00 (s, 2H), 3.77 (s, 6H), 3.76 (s,
6H) ppm; 13C{1H}NMR (100 MHz, DMSO-d6): δ 160.0, 159.9, 130.2, 129.9, 124.6, 124.5, 119.2, 119.1,
114.7, 55.6, 41.1 ppm; IR: υmax 3398, 2969, 2839, 2245, 1614, 1515, 1250, 1032, 821 cm-1; HRMS
(ESI) m/z: calcd. for C18H16N2O2Na [M+Na]+ 315.1110, found: 315.1102.
Characterization data for polysubstituted 2-aminopyrroles (Compound 3a-v, Table 2)
2-Amino-3-(4-methoxyphenyl)-1H-pyrrole-4,5-dicarbonitrile (3a, Table 2):
Dark brown solid, 214 mg, 90%, m.p. 184-186 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 8.4 Hz,
13
2H), 7.01 (d, J = 8.7 Hz, 2H), 5.64 (s, 2H), 3.77 (s, 2H) ppm; C NMR (100 MHz, DMSO-d6): δ 158.6,
141.3, 129.4, 124.1, 115.1, 114.9, 113.8, 107.1, 101.7, 97.4, 55.6 ppm; IR: υmax 3350, 2208, 1634, 1247,
1177 cm-1; HRMS (ESI) m/z: calcd. for C13H10N4ONa [M+Na]+ 261.0753, found: 261.0746.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 28
1
2
3
4
2-Amino-3-(2-methoxyphenyl)-1H-pyrrole-4,5-dicarbonitrile (3b, Table 2):
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Brown solid, 200 mg, 84%, m.p. 144-146 °C; H NMR (400 MHz, DMSO-d6): δ 7.33 (dt, J = 8.1 Hz, J =
1.7 Hz, 1H), 7.24 (dd, J = 7.5 Hz, J = 1.7 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.00 (dt, J = 7.4 Hz, J = 0.8
13
Hz, 1H), 5.42 (s, 2H), 3.79 (s, 3H) ppm; C NMR (100 MHz, DMSO-d6): δ 156.8, 142.4, 131.0, 129.3,
121.0, 120.3, 115.1, 114.2, 111.9, 104.3, 103.3, 97.9, 55.7 ppm; IR: υmax 3408, 3334, 3235, 2231, 2206,
1260, 1015cm-1; HRMS (ESI) m/z: calcd. for C13H11N4O [M+H]+ 239.0933, found: 239.0925.
2-Amino-3-(3,4,5-trimethoxyphenyl)-1H-pyrrole-4,5-dicarbonitrile (3c, Table 2):
1
Dark brown solid, 241 mg, 81%, m.p. 85-87 °C; H NMR (400 MHz, DMSO-d6): δ 6.69 (s, 2H), 3.80 (s,
9H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 153.5, 141.8, 136.7, 127.5, 115.2, 113.8, 107.0, 105.3,
101.7, 97.9, 60.5, 56.2 ppm; IR: υmax 3338, 2209, 1598, 1128, 735 cm-1; HRMS (ESI) m/z: calcd. for
C15H15N4O3 [M+H]+ 299.1144, found: 299.1141.
2-Amino-3-(2,4,6-trimethoxyphenyl)-1H-pyrrole-4,5-dicarbonitrile (3d, Table 2):
ACS Paragon Plus Environment

Page 13 of 28
The Journal of Organic Chemistry
1
2
3
4
5
1
Dark brown solid, 238 mg, 80%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 6.29 (s,
2H), 5.14 (s, 2H), 3.82 (s, 3H), 3.73 (s, 6H) ppm; C{1H}NMR (100 MHz, DMSO-d6): δ 161.5, 159.0,
13
6
7
8
142.4, 115.0, 114.1, 105.2, 100.5, 100.4, 96.1, 91.3, 55.9, 55.7 ppm; IR: υmax 3426, 3346, 2229, 2207,
9
1630, 1275, 1109 cm-1. HRMS (ESI) m/z: calcd. for C15H15N4O3 [M+H]+ 299.1144, found: 299.1146.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Amino-3-(4-hydroxyphenyl)-1H-pyrrole-4,5-dicarbonitrile (3e, Table 2):
1
Red solid, 204 mg, 91%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 7.22 (d, J = 8.4
13
Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.59 (s, 2H) ppm; C NMR (100 MHz, DMSO-d6): δ 156.8, 141.2,
129.4, 122.5, 116.2, 115.2, 113.9, 107.6, 101.6, 97.2 ppm; IR: υmax 3390, 3350, 2209, 1627, 1249 cm-1;
HRMS (ESI) m/z: calcd. for C12H9N4O [M+Na]+ 247.0596, found: 247.0583.
2-Amino-3-(p-tolyl)-1H-pyrrole-4,5-dicarbonitrile (3f, Table 2):
1
Brown solid, 191 mg, 86%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 12.1 (s, 1H), 7.32 (d, J =
13
7.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 5.75 (s, 2H), 2.33 (s, 3H) ppm; C NMR (100 MHz, DMSO-d6): δ
141.5, 136.4, 129.9, 128.9, 127.9, 115.0, 113.7, 106.9, 101.7, 97.7, 21.2 ppm; IR: υmax 3443, 3334, 3224,
2237, 2208, 1628, 1286 cm-1; HRMS (ESI) m/z: calcd. for C13H10N4Na [M+Na]+ 245.0803, found:
245.0801.
2-Amino-3-phenyl-1H-pyrrole-4,5-dicarbonitrile (3g, Table 2):
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Brown solid, 175 mg, 84%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 7.44-7.31 (m,
5H), 5.82 (s, 2H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 141.6, 131.9, 129.3, 127.9, 127.1, 115.0,
113.6, 106.7, 101.7, 98.0 ppm; IR: υmax 3404, 3330, 3248, 2229, 2215, 1638, 1276 cm-1; HRMS (ESI)
m/z: calcd. for C12H8N4Na [M+Na]+ 231.0647, found: 231.0646.
2-Amino-3-(4-(dimethylamino)phenyl)-1H-pyrrole-4,5-dicarbonitrile (3h, Table 2):
Dark brown solid, 191 mg, 76%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 7.25 (d,
13
J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 5.55 (s, 2H), 2.92 (s, 6H) ppm; C NMR (100 MHz, DMSO-
d6): δ 149.9, 139.9, 128.3, 119.4, 114.1, 112.9, 112.5, 108.8, 101.6, 97.0, 39.4 ppm; IR: υmax 3478, 3386,
3250, 2229, 2212, 1613 cm-1; HRMS (ESI) m/z: calcd. for C14H14N5 [M+H]+ 252.1249, found: 252.1249.
2-Amino-3-(4-bromophenyl)-1H-pyrrole-4,5-dicarbonitrile (3i, Table 2):
Dark brown solid, 225 mg, 79%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 7.63 (d,
13
J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 5.91 (s, 2H) ppm; C NMR (100 MHz, DMSO-d6): δ 141.8,
ACS Paragon Plus Environment

Page 15 of 28
The Journal of Organic Chemistry
1
2
3
4
132.3, 131.2, 130.0, 120.0, 114.8, 113.5, 105.3, 101.6, 98.3 ppm; IR: υmax 3468, 3379, 3241, 2233, 2208,
1618, 1267, 750 cm-1; HRMS (ESI) m/z: calcd. for C12H7BrN4Na [M+Na]+ 308.9752, found: 308.9749.
5
6
7
8
9
2-Amino-3-(4-chlorophenyl)-1H-pyrrole-4,5-dicarbonitrile (3j, Table 2):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Dark red solid, 200 mg, 83%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 7.50 (d, J =
8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 5.91 (s, 2H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 141.8, 131.5,
130.8, 129.7, 129.3, 114.8, 113.5, 105.3, 101.7, 98.3 ppm; IR: υmax 3470, 3388, 3243, 2221, 2208, 1623,
1269, 827 cm-1; HRMS (ESI) m/z: calcd. for C12H7ClN4Na [M+Na]+ 265.0257, found: 265.0249.
2-Amino-3-(4-fluorophenyl)-1H-pyrrole-4,5-dicarbonitrile (3k, Table 2):
1
Light brown solid, 181 mg, 80%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 7.47-
7.44 (m, 2H), 7.28 (dd, J = 8.8 Hz, J = 8.8 Hz, 2H), 5.82 (s, 2H) ppm; 13C NMR (100 MHz, DMSO-d6): δ
161.3 (d, JC-F = 242 Hz), 141.6, 130.1 (d, JC-C-C-F = 8 Hz), 128.3 (d, JC-C-C-C-F = 3 Hz), 116.2 (d, JC-C-F = 22
Hz), 114.9, 113.5, 105.8, 101.8, 97.8 ppm; IR: υmax 3450, 3353, 2215, 1624, 1217 cm-1. HRMS (ESI) m/z:
calcd. for C12H8FN4 [M+H]+ 227.0733, found: 227.0726
2-Amino-3-(4-cyanophenyl)-1H-pyrrole-4,5-dicarbonitrile (3l, Table 2):
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Dark brown solid, 151 mg, 65%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 8.00 (d,
13
J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 6.83 (s, 2H) ppm; C NMR (100 MHz, DMSO-d6): δ 151.1,
135.7, 134.2, 133.4, 128.5, 119.0, 116.1, 114.8, 111.4, 91.4, 72.5 ppm; IR: υmax 3437, 3348, 3226, 2208,
1636, 1247 cm-1. HRMS (ESI) m/z: calcd. for C13H8N5 [M+H]+ 234.0780, found: 234.0787.
2-Amino-3-(4-nitrophenyl)-1H-pyrrole-4,5-dicarbonitrile (3m, Table 2):
1
Red solid, 160 mg, 63%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 8.39 (d, J = 7.6
13
Hz, 2H), 7.99 (d, J = 7.6 Hz, 2H), 6.11 (s, 2H) ppm; C NMR (100 MHz, DMSO-d6): δ 149.0, 147.6,
136.9, 134.8, 127.4, 124.9, 115.5, 114.3, 87.0, 81.3 ppm; IR: υmax 3450, 3363, 3252, 2206, 1637, 1341,
1270 cm-1; HRMS (ESI) m/z: calcd. for C12H7N5O2Na [M+Na]+ 276.0498, found: 276.0493.
2-Amino-3-(naphthalen-2-yl)-1H-pyrrole-4,5-dicarbonitrile (3n, Table 2):
ACS Paragon Plus Environment

Page 17 of 28
The Journal of Organic Chemistry
1
2
3
4
1
Buff solid, 211 mg, 82%, m.p. 145-147 °C; H NMR (400 MHz, DMSO-d6): δ 8.00-7.95 (m, 1H), 7.68-
7.66 (m, 1H), 7.59-7.52 (m, 3H), 7.44 (dd, J = 7.0 Hz, J = 0.8 Hz, 1H), 5.46 (s, 2H) ppm; 13C NMR (100
MHz, DMSO-d6): δ 142.4, 134.0, 131.9, 129.2, 128.9, 128.8, 126.9, 126.6, 126.2, 125.7, 114.7, 113.8,
105.4, 104.1, 97.5 ppm; IR: υmax 3445, 3352, 3231, 2234, 2208, 1620, 1276 cm-1; HRMS (ESI) m/z: calcd.
for C16H10N4Na [M+Na]+ 281.0803, found: 281.0797.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Amino-3-propyl-1H-pyrrole-4,5-dicarbonitrile (3o, Table 2):
1
Dark brown solid, 104 mg, 60%, m.p. 163-165 °C; H NMR (400 MHz, DMSO-d6): 4.06 (s, 2H), 2.34 (t,
13
J = 7.3 Hz, 2H), 1.49-1.40 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H) ppm; C NMR (100 MHz, DMSO-d6): δ
141.7, 114.7, 113.9, 107.2, 103.1, 94.9, 25.4, 23.1, 13.7 ppm; IR: υmax 3449, 3360, 2238, 2202, 1624,
1274 cm-1. HRMS (ESI) m/z: calcd. for C9H11N4 [M+H]+ 175.0984, found: 175.0980.
5-Amino-4-heptyl-1H-pyrrole-2,3-dicarbonitrile (3p, Table 2):
1
Dark brown solid, 164 mg, 71%, m.p. 112-114 °C; H NMR (400 MHz, DMSO-d6): 11.90 (s,1H), 5.53
(s, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.46-1.41 (m, 2H), 1.24 (s, 8H), 0.85 (t, J = 6.7 Hz, 3H ) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 141.9, 114.8, 114.1, 107.4, 103.0, 95.0, 31.7, 29.8, 28.9, 28.8, 23.4, 22.5, 14.4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 28
1
2
3
4
5
ppm; IR: υmax 3350, 2924, 2206, 1595, 1496, 1275, 1082, 750 cm-1. MS (ESI) calcd. for C13H19N4 [M+H]+
231.1, found: 231.1.
6
7
8
9
5-Amino-4-phenethyl-1H-pyrrole-2,3-dicarbonitrile (3q, Table 2):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Light brown solid, 155 mg, 66%, m.p. 123-125 °C; H NMR (400 MHz, DMSO-d6): 11.91 (s, 1H), 7.29-
13
7.25(m, 2H), 7.21-7.18 (m, 3H) 5.62 (s, 2H), 2.74-2.70 (m, 2H), 2.67-2.63 (m, 2H) ppm; C NMR (100
MHz, DMSO-d6): δ 142.0, 141.4, 128.8, 128.6, 126.4, 114.6, 114.0, 106.4, 103.2, 95.1, 35.7, 25.7 ppm;
IR: υmax 3347, 2209, 1626, 1500, 1416, 1287, 1080, 702 cm-1. MS (ESI) calcd. for C14H12N4Na [M+Na]+
259.0, found: 259.0.
2-Amino-3-(pyridin-3-yl)-1H-pyrrole-4,5-dicarbonitrile (3r, Table 2):
1
Pale white solid, 106 mg, 51%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 8.74 (d, J = 1.8 Hz,
1H), 8.62 (dd, J = 4.8 Hz, J = 1.4 Hz, 1H), 7.95 (dt, J = 4.9 Hz, J = 1.8 Hz), 7.55 (dd, J = 7.9 Hz, J = 4.8
Hz, 1H), 6.78 (s, 2H) ppm; 13C{1H}NMR (100 MHz, DMSO-d6): δ 150.9, 149.9, 148.2, 135.4, 133.1,
127.3, 124.5, 116.2, 114.9, 91.1, 72.8 ppm; IR: υmax 3406, 3335, 3218, 2204, 1646, 1540, 1254 cm-1;
HRMS (ESI) m/z: calcd. for C11H8N5 [M+H]+ 210.0779, found: 210.0777.
2-Amino-3-(1H-indol-3-yl)-1H-pyrrole-4,5-dicarbonitrile (3s, Table 2):
ACS Paragon Plus Environment

Page 19 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Black solid, 99 mg, 40%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 7.48-7.41 (m,
13
3H), 7.14 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 5.45 (s, 2H), 4.47 (s, 1H) ppm; C NMR (100
MHz, DMSO-d6): δ 141.9, 136.6, 126.4, 124.9, 121.9, 119.8, 112.2, 105.1, 63.2 ppm; IR: υmax 2924,
2215, 1713, 1462, 804 cm-1.MS (ESI) m/z: calcd. for C14H9N5 Na [M+Na]+ 270.0, found: 270.0.
2-Amino-3-(thiophen-2-yl)-1H-pyrrole-4,5-dicarbonitrile (3t, Table 2):
Black solid, 79 mg, 37%, m.p. >200 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 7.61 (d, J = 5.0
Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.16 (t, J = 3.9 Hz, 1H), 6.67 (s, 2H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 150.9, 132.1, 129.7, 128.4, 127.3, 126.5, 116.4, 115.2, 89.8, 72.1 ppm; IR: υmax 3333, 2199,
1613 cm-1. MS (ESI) calcd. for C10H6N4SNa [M+Na]+ 237.0, found: 237.0.
Ethyl 2-amino-5-cyano-3-(4-methoxyphenyl)-1H-pyrrole-4-carboxylate (3u, Table 2):
1
Light orange solid, 117 mg, 41%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 7.15
(d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.04 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 1.10 (t,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 28
1
2
3
13
7.1 Hz, 3H) ppm; C NMR (100 MHz, DMSO-d6): δ 162.8, 158.1, 141.4, 131.6, 125.6, 122.2, 115.3,
113.8, 106.1, 94.7, 60.2, 55.5, 14.3 ppm; IR: υmax 3215, 2926, 2201, 1717, 1658, 1275, 1175 cm-1. HRMS
(ESI) m/z: calcd. for C15H16N3O3 [M+H]+ 286.1192, found: 286.1188.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 2-amino-3-(4-chlorophenyl)-5-cyano-1H-pyrrole-4-carboxylate (3v, Table 2):
1
Light orange solid, 115 mg, 40%, m.p. >200 °C; H NMR (400 MHz, DMSO-d6): δ 7.37 (d, J = 8.4 Hz,
2H), 7.24 (d, J = 8.4 Hz, 2H), 5.24 (s, 2H), 4.09 (q, J = 7.1, 2H), 1.11 (t, J = 7.1, 2H) ppm; 13C{1H}NMR
(100 MHz, DMSO-d6): δ 162.14, 141.26, 131.96, 131.76, 130.54, 127.71, 121.56, 114.57, 104.23, 94.89,
59.83, 13.71 ppm; IR: υmax 3475, 3377, 2211, 1663, 1614, 1508, 1310, 1220, 835, 701 cm-1; HRMS
(ESI) m/z: calcd. for C14H12ClN3O2Na [M+Na]+ 312.0516, found: 312.0506.
Characterization
Data
for
2-(4-chlorophenyl)-8-(4-methoxyphenyl)-4-phenylpyrrolo[1,2-
a]pyrimidine-6,7-dicarbonitrile (4a, Scheme 3)
2-(4-chlorophenyl)-8-(4-methoxyphenyl)-4-phenylpyrrolo[1,2-a]pyrimidine-6,7-dicarbonitrile (4a,
Scheme 3)
Yellow solid, 142 mg, 62%, m.p. >200 °C; 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.6 Hz, 2H), 8.04
(d, J = 8.8 Hz, 2H), 7.74 (dd, J = 7.3, 7.3 Hz, 1H), 7.67 (dd, J = 7.7, 7.3 Hz, 2H), 7.61 (d, J = 7.3 Hz,
ACS Paragon Plus Environment

Page 21 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
2H), 7.52 (d, J = 8.6 Hz, 2H), 7.35 (s, 1H), 7.13 (d, J = 8.8 Hz, 2H), 3.93(s, 3H), ppm; C NMR (100
MHz, CDCl3): δ 159.8, 154.3, 146.7, 139.8, 137.7, 134.2, 132.2, 130.2, 130.1, 129.5, 129.3, 129.1, 128.5,
122.3, 119.2, 114.4, 113.3, 109.8, 109.5, 108.3, 96.7, 55.4 ppm; IR: υmax 2956, 2839, 2250, 2208, 1618,
1459, 1275, 1260, 750 cm-1; HRMS (ESI) m/z: calcd. for C28H18Cl35N4O [M+H]+ 461.1169, found:
461.1184.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
X-ray crystal details for compound 3f and 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: skguchhait@niper.ac.in
Author Contributions
§S.S. and M.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from CSIR and DST, New Delhi, for this investigation. NH
is thankful to DST, New Delhi, for DST INSPIRE fellowship. MS is thankful to UGC for fellowship. VC
is thankful to CSIR for fellowship.
REFERENCES
(1) (a) O’Hagan, D. Pyrrole, Pyrrolidine, Pyridine, Piperidine and Tropane Alkaloids. Nat. Prod. Rep.
2000, 17, 435. (b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Lamellarins and Related Pyrrole-Derived
Alkaloids from Marine Organisms. Chem. Rev. 2008, 108, 264. (c) La Regina, G.; Silvestri, R.; Artico,
M.; Lavecchia, A.; Novellino, E.; Befani, O.; Turini, P.; Agostinelli, E. New Pyrrole Inhibitors of
Monoamine Oxidase:ꢀ Synthesis, Biological Evaluation, and Structural Determinants of MAO-A and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 28
1
2
3
4
5
6
MAO-B Selectivity. J. Med. Chem. 2007, 50, 922. (d) Huffman, J. W. Cannabimimetic Indoles, Pyrroles
and Indenes. Curr. Med. Chem. 1999, 6, 705.
7
8
9
(2) (a) Jones, R. A. Pyrroles, The Synthesis, Reactivity, and Physical Properties of Substituted Pyrroles,
Part II. Ed.; Wiley: New York, NY 1992. (b) Butler, R. N.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Comprehensive Heterocyclic Chemistry. Katritzky, AR, Rees, CW, Scriven, EFV, Ed. 1996.
(3) (a) Wallace, M. B.; Adams, M. E.; Kanouni, T.; Mol, C. D.; Dougan, D. R.; Feher, V. A.; O’Connell, S.
M.; Shi, L.; Halkowycz, P.; Dong, Q. Structure-Based Design and Synthesis of Pyrrole Derivatives as
MEK Inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 4156. (b) Onnis, V.; De Logu, A.; Cocco, M. T.;
Fadda, R.; Meleddu, R.; Congju, C. 2-Acylhydrazino-5-arylpyrrole Derivatives: Synthesis and Antifungal
Activity Evaluation. Eur. J. Med. Chem. 2009, 44, 1288. (c) Cocco, M. T.; Congiu, C.; Onnis, V.
Synthesis and In vitro Antitumoral Activity of New N-phenyl-3-pyrrolecarbothioamides. Bioorg. Med.
Chem. 2003, 11, 495.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Tsuda, M.; Nozawa, K.; Shimbo, K.; Kobayashi, J. I. Rigidins B−D, New Pyrrolopyrimidine Alkaloids
from a Tunicate Cystodytes Species. J. Nat. Prod. 2003, 66, 292.
(5) (a) Gangjee, A.; Jain, H. D.; Queener, S. F.; Kisliuk, R. L. The Effect of 5-Alkyl Modification on the
Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as
Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents.
J.Med. Chem. 2008, 51, 4589. (b) Bookser, B.C.; Ugarkar, B.G.; Matelich, M.C.; Lemus, R.H.; Allan, M.;
Tsuchiya, M.; Nakane, M.; Nagahisa, A.; Wiesner, J.B.; Erion, M.D. Adenosine Kinase Inhibitors. 6.
Synthesis, Water Solubility, and Antinociceptive Activity of 5-Phenyl-7-(5-deoxy-β-d-
ribofuranosyl)pyrrolo[2,3-d]pyrimidines Substituted at C4 with Glycinamides and Related Compounds.
J. Med. Chem. 2005, 48, 7808.
(6) Migawa, M. T.; Drach, J. C.; Townsend, L. B. Design, Synthesis and Antiviral Activity of Novel 4,5-
Disubstituted 7-(β-d-Ribofuranosyl)pyrrolo[2,3-d][1,2,3]triazines and the Novel 3-Amino-5-methyl-1-(β-
d-ribofuranosyl)-
and
3-Amino-5-methyl-1-(2-deoxy-β-d-ribofuranosyl)-1,5-dihydro-1,4,5,6,7,8-
hexaazaacenaphthylene as Analogues of Triciribine. J. Med. Chem. 2005, 48, 3840.
ACS Paragon Plus Environment

Page 23 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(7) Allegretti, M.; Anacardio, R.; Cesta, M.C.; Curti, R.; Mantovanini, M.; Nano, G.; Topai, A.; Zampella,
G. A Practical Synthesis of 7-Azaindolylcarboxy-endo-tropanamide (DF 1012). Org. Proc. Res.
Dev. 2003, 7, 209.
9
(8) (a) Piloty, O.Synthese von Pyridin-Derivaten aus Dichlor-äther und β-Amino-crotonsäureester. Ber.
Dtsch. Chem. Ges. 1910, 43, 489. (b) Robinson, R.; Robinson, G. M. LIV.—A New Synthesis of
Tetraphenylpyrrole. J. Chem. Soc. Trans. 1918, 113, 639. (c) Milgram, B. C.; Eskildsen, K.; Richter, S.
M.; Scheidt, W. R.; Scheidt, K. A. Microwave-Assisted Piloty−Robinson Synthesis of 3,4-Disubstituted
Pyrroles. J. Org. Chem. 2007, 72, 3941.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Manley, J. M.; Kalman, M. J.; Conway, B. G.; Ball, C. C.; Havens, J. L.; Vaidyanathan, R. Early
Amidation Approach to 3-[(4-Amido)pyrrol-2-yl]-2-indolinones. J. Org. Chem. 2003, 68, 6447.
(10) Banik, B. K.; Samajdar, S.; Banik, I. Simple Synthesis of Substituted Pyrroles. J. Org.
Chem. 2004, 69, 213.
(11) Moss, T. A.; Nowak, T. Synthesis of 2,3-dicarbonylated Pyrroles and Furans via the Three-
Component Hantzsch reaction. Tetrahedron Lett. 2012, 53, 3056.
(12) (a) Estévez, V.; Villacampa, M.; Menéndez, J. C. Recent Advances in the Synthesis of Pyrroles by
Multicomponent Reactions. Chem. Soc. Rev. 2014, 43, 4633. (b) Galenko, E. E.; Bodunov, V. A.;
Galenko, A. V.; Novikov, M. S.; Khlebnikov, A. F. Fe(II)-Catalyzed Isomerization of 4-Vinylisoxazoles
into Pyrroles. J. Org. Chem. 2017, 82, 8568.
(13) (a) Reekie, T. A.; Donckele, E. J.; Manenti, G.; Püntener, S.; Trapp, N.; Diederich, F. A Three-Step
Synthesis of Tetrasubstituted NH-Pyrroles. Org. Lett. 2016, 18, 2252. (b) Chien, T. C.; Meade, E. A.;
Hinkley, J. M.; Townsend, L. B. Facile Synthesis of 1-Substituted 2-Amino-3-cyanopyrroles:ꢀ New
Synthetic Precursors for 5,6-Unsubstituted Pyrrolo[2,3-d]pyrimidines. Org. Lett. 2004, 6, 2857. (c)
Demir, A. S.; Emrullahoglu, M. Zinc Perchlorate Catalyzed One-pot Amination–annulation of α-
Cyanomethyl-β-ketoesters in Water. Regioselective Synthesis of 2-aminopyrrole-4-carboxylates
Tetrahedron, 2006, 62, 1452. (d) Demir, A. S.; Emrullahoglu, M. An Effective New Synthesis of 2-
Aminopyrrole-4-carboxylates. Tetrahedron, 2005, 61, 10482.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 28
1
2
3
4
5
6
7
8
9
(14) (a) Qiu, G.; Wang, Q.; Zhu, J. Palladium-Catalyzed Three-Component Reaction of Propargyl
Carbonates, Isocyanides, and Alcohols or Water: Switchable Synthesis of Pyrroles and Its Bicyclic
Analogues.Org. Lett. 2016, 19, 270 (b) Wu, Y.; Zhu, L.; Yu, Y.; Luo, X.; Huang, X. Polysubstituted 2-
Aminopyrrole Synthesis via Gold-Catalyzed Intermolecular Nitrene Transfer from Vinyl Azide to
Ynamide: Reaction Scope and Mechanistic Insights. J. Org. Chem. 2015, 80, 11407. (c) Xiao, X. Y.;
Zhou, A. H.; Shu, C.; Pan, F.; Li, T.; Ye, L. W. Atom-Economic Synthesis of Fully Substituted 2-
Aminopyrroles via Gold-Catalyzed Formal [3+2] Cycloaddition between Ynamides and Isoxazoles.
Chem. Asian J. 2015, 10, 1854. (d) Demir, A. S.; Emrullahoğlu, M.; Buran, K. Gold(I)/Zn(II) Catalyzed
Tandem Hydroamination/annulation Reaction of 4-yne-nitriles. Chem. Commun. 2010, 46, 8032.
(15) (a) Wang, X.; Wang, S. Y.; Ji, S. J. Chemoselective Synthesis of Polycyclic Spiroindolines and
Polysubstituted Pyrroles via the Domino Reaction of 2-Isocyanoethylindoles. J. Org. Chem. 2014, 79,
8577. (b) Wang, X.; Xu, X. P.; Wang, S. Y.; Zhou, W.; Ji, S. J. Highly Efficient Chemoselective Synthesis
of Polysubstituted Pyrroles via Isocyanide-Based Multicomponent Domino Reaction. Org. Lett. 2013, 15,
4246. (c) Nair, V.; Vinod, A. U.; Rajesh, C. A Novel Synthesis of 2-Aminopyrroles Using a Three-
Component Reaction. J. Org. Chem. 2001, 66, 4427.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) (a) Qi, X.; Xiang, H.; He, Q.; Yang, C. Synthesis of Multisubstituted 2-Aminopyrroles/pyridines via
Chemoselective Michael Addition/Intramolecular Cyclization Reaction. Org. Lett. 2014, 16, 4186. (b)
Frolova, L. V.; Evdokimov, N. M.; Hayden, K.; Malik, I.; Rogelj, S.; Kornienko, A.; Magedov, I. V. One-
Pot Multicomponent Synthesis of Diversely Substituted 2-Aminopyrroles. A Short General Synthesis of
Rigidins A, B, C, and D. Org. Lett. 2011, 13, 1118.
(17) Das, P.; Ray, S.; Mukhopadhyay, C. Exploitation of Dual Character of CN Moiety in the Synthesis of
Uniquely Decorated 3H-Pyrroles: A Rare Observation. Org. Lett. 2013, 15, 5622.
(18) McMurry, J. E.; Fleming, M. P. Improved Procedures for the Reductive Coupling of Carbonyls to
Olefins and for the Reduction of Diols to Olefins. J. Org. Chem. 1976, 41, 896.
ACS Paragon Plus Environment

Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(19) Swindell, C. S.; Chander, M. C.; Heerding, J. M.; Klimko, P. G.; Rahman, L. T.; Raman, V.;
Venkataraman, H. Taxane Synthesis through Intramolecular Pinacol Coupling at C-1−C-2. Construction
and Oxidative Transformations of a C-Aromatic Taxane Diene. J. Org. Chem. 1996, 61, 1101.
(20) Cram, D. J.; Gaston, L. K. Macro Rings. XXII. 6-Hydroxy-7-keto-trans-cyclodecene and
Derivatives. J. Am. Chem. Soc. 1960, 82, 6386.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(21) Hachisu, Y.; Bode, J. W.; Suzuki, K. Catalytic Intramolecular Crossed Aldehyde− Ketone Benzoin
Reactions: A Novel Synthesis of Functionalized Preanthraquinones. J. Am. Chem. Soc. 2003, 125, 8432.
(22) Maugein, N.; Wagner, A.; Mioskowski, C. Synthesis of Medium- and Large-Size Rings by
Intramolecular Nitrile Oxide Dimerization: An Efficient C-C Bond-Forming Ring-Closing Reaction J.
Org. Chem. 1999, 64, 8428.
(23) Anbarasan, P.; Schareina, T.; Beller, M. Recent Developments and Perspectives in Palladium-
Catalyzed Cyanation of Aryl halides: Synthesis of Benzonitriles. Chem. Soc. Rev. 2011, 40, 5049.
(24) (a) Maurya, H. K.; Gupta, A. A Convenient Synthesis of Pyrimidinone and Pyrimidine Containing
Bisheteroarenes and Analogs. RSC Adv. 2014, 4, 22106. (b) Younis, Y.; Douelle, F.; Feng, T. S.; Cabrera,
D. G.; Manach, C. L.; Nchinda, A. T.; Mannila, J. 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally
Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential. J. Med
Chem. 2012, 55, 3479. (c) Huang, H.; Guzman-Perez, A.; Acquaviva, L.; Berry, V.; Bregman, H.; Dovey,
J. Structure-Based Design of 2-Aminopyridine Oxazolidinones as Potent and Selective Tankyrase
Inhibitors. ACS Med. Chem. Lett. 2013, 4, 1218.
(25) (a) Evans, D. A.; Truesdale L. K. Carbonyl Insertion Reactions of Silicon Pseudohalides: Catalysis.
Tetrahedron Lett. 1973, 49, 4929. (b) Evans D.A.; Carroll, G. L.; Truesdale L. K. Synthetic Applications
of Trimethylsilyl cyanide. Efficient synthesis of. Beta.-aminomethyl Alcohols. J. Org. Chem. 1974, 39,
914.
(26) (a) Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. Total Synthesis of Gelsemoxonine. J.
Am. Chem. Soc. 2011, 133, 17634. (b) Kaise , H.; Shimokawa, J.; Fukuyama, T. TMSCN/DBU-Mediated
Facile Redox Transformation of α,β-Unsaturated Aldehydes to Carboxylic Acid Derivatives. Org. Lett.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
6
7
8
9
2014, 16, 727. (c) Guchhait, S. K.; Priyadarshani, G.; Gulghane, N. M. RSC Adv. 2016, 6, 56056. (d)
Guchhait, S. K.; Chaudhary, V. A Reaction of 1,2-Diamines and Aldehydes with Silyl Cyanide as Cyanide
Pronucleophile to Access 2-Aminopyrazines and 2-Aminoquinoxalines. Org. Biomol. Chem. 2014, 12,
6694. (e) Guchhait, S. K.; Chaudhary, V.; Madaan, C. A Chemoselective Ugi-type Reaction in Water using
TMSCN as a Functional Isonitrile Equivalent: Generation of Heteroaromatic Molecular Diversity. Org.
Biomol. Chem. 2012, 10, 9271.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(27) (a) Prakash, S. G.; Vaghoo, H.; Panja, C.; Surampudi, V.; Kultyshev, R.; Mathew, T.; Olah, G. A.
Effect of Carbonates/Phosphates as Nucleophilic Catalysts in Dimethylformamide for Efficient
Cyanosilylation of Aldehydes and Ketones. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 3026. (b) Prakash G.
K. S.; Panja C,; Vaghoo H,; Surampudi V,; Kultyshev, R.; Mandal M.; Rasul, G.; Mathew, T.; Olah, G. A.
Facile Synthesis of TMS-Protected Trifluoromethylated Alcohols Using Trifluoromethyltrimethylsilane
(TMSCF3) and Various Nucleophilic Catalysts in DMF. J. Org. Chem. 2006, 71, 6806–6813.
(28) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. A Catalytic Asymmetric
Strecker-type Reaction: Interesting Reactivity Difference between TMSCN and HCN. Angew. Chem. Int.
Ed. Engl. 2000, 39, 1650.
(29) Chebolu, R.; Kommi, D. N.; Kumar, D.; Bollineni, N.; Chakraborti, A. K. Hydrogen-Bond-Driven
Electrophilic Activation for Selectivity Control: Scope and Limitations of Fluorous Alcohol-Promoted
Selective Formation of 1,2-Disubstituted Benzimidazoles and Mechanistic Insight for Rationale of
Selectivity. J. Org. Chem. 2012, 77, 10158.
(30) (a) Kim, J.; Kim, H. J.; Chang S. Synthesis of Aromatic Nitriles Using Nonmetallic Cyano-Group
Sources. Angew. Chem. Int. Ed. 2012, 51,11948. (b) Martinez-Ariza, G.; Mehari, B. T.; Pinho, L. A.
G.; Foley, C.; Day, K.; Jewett, J. C.; Hulme, C. Synthesis of Fluorescent Heterocycles via a
Knoevenagel/[4 + 1]-Cycloaddition Cascade using Acetyl Cyanide. Org. Biomol. Chem. 2017, 15, 6076.
(c) Wen, Q.; Jin , J.; Zhang. L.; Luo, Y.; Lu, P.; Wang, Y. Copper-Mediated Cyanation Reactions.
Tetrahedron Lett. 2014, 55, 1271.
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(31) (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. Cyanosilylation of Aldehydes and Ketones. A
Convenient Route to Cyanohydrin Derivatives. Chem Commun. 1973, 2, 55. (b) Lidy, W.; Sundermeyer,
W. Cleavage Reactions of Trimethylsilyl Cyanide, a New Presentation Method for O- (Trimethylsilyl)
cyanohydrins. Eur. J. Inorg. Chem. 1973, 106, 587.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(32) (a) Leblanc, J. P.; Gibson, H. W. Synthesis of α-Aminonitriles by Self-Catalyzed, Stoichiometric
Reaction of Primary Amines, Aldehydes, and Trimethylsily Cyanide. Tetrahedron Lett. 1992, 33, 6295.(b)
Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions. Angew. Chem. Int. Ed.
2001, 40, 875.
(33) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. Enantioselective Construction of Quaternary
Stereocenter through a Reissert-Type Reaction Catalyzed by an Electronically Tuned Bifunctional
Catalyst:ꢀ Efficient Synthesis of Various Biologically Significant Compounds. J. Am. Chem. Soc.
2001, 123, 10784.
(34) Wu, J.; Hou, X. L.; Dai, L. Effective Ring-Opening Reaction of Aziridines with Trimethylsilyl
Compounds:ꢀ A Facile Access to β-Amino Acids and 1,2-Diamine Derivatives. J. Org. Chem. 2000, 65,
1344.
(35) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J.; Snapper, M. L.; Hoveyda, A. H. Discovery
of Chiral Catalysts through Ligand Diversity: Ti-Catalyzed Enantioselective Addition of TMSCN to meso
Epoxides. Angew. Chem. Int. Ed. 1996, 35, 1668.
(36) Okino, T.; Hoashi, Y.; Takemoto, Y. Thiourea-Catalyzed Nucleophilic Addition of TMSCN and
Ketene Silyl Acetals to Nitrones and Aldehydes. Tetrahedron Lett. 2003, 44, 2817.
(37) Peterson, L. I. Meso-dl Isomerization of 2,3-Dimethyl-2,3-diphenylsuccinonitrile. J. Am. Chem.
Soc. 1967, 89, 2677.
(38) Qi, C.; Hu, X.; Jiang, H. Copper-Mediated C–H Cyanation of (Hetero)arenes with Ethyl
(Ethoxymethylene)Cyanoacetate as a Cyanating Agent. Chem. Commun. 2017, 53, 7994.
(39) (a) Ye, T. Y.; Selvaraju, M.; Sun, C. M. Cascade Synthesis of Benzimidazole-Linked Pyrroles via
Copper Catalyzed Oxidative Cyclization and Ketonization. Org. Lett. 2017, 19, 3103. (b) Kumar, P. M.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
6
7
8
Kumar, K. S.; Mohakhud, P. K.; K. Mukkanti, R.; Kapavarapu, Parsa K. V. L.; Pal, M. (Pd/C-
mediated)Coupling–Iodocyclization–Coupling Strategy in Discovery of Novel PDE4 Inhibitors: A New
Synthesis of Pyrazolopyrimidines. Med. Chem. Commun. 2012, 48, 431.
9
(40) Mohamed, M.S.; Kamel, R.; Fatahala, S.S. Synthesis and Biological Evaluation of Some Thio
Containing Pyrrolo [2,3-d]Pyrimidine Derivatives for their Anti-inflammatory and Anti-microbial
Activities. Eur. J. Med. Chem. 2010, 45, 2994.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(41) Yu, Y.-Q. and Wang, Z.-L. A Simple, Efficient and Green Procedure for Knoevenagel Condensation
in Water or Under Solvent-free Conditions. J. Chin. Chem. Soc. 2013, 60, 288.
ACS Paragon Plus Environment