An efficient synthesis of 2-aminopyrroles from enaminone-amidine adduct and phenacyl/benzyl/heteroalkyl-halides

Article abstract of DOI:10.1016/j.tetlet.2011.08.149

Herein, we report an efficient and facile synthesis of substituted 2-aminopyrroles from the reaction of enaminone-amidine adduct and various phenacyl, benzyl, or heteroalkyl halides in the presence of 1,8-diazabicyclo[5. 4.0]undec-7-ene (DBU) in good to e

Full text of DOI:10.1016/j.tetlet.2011.08.149

Tetrahedron Letters 52 (2011) 6331–6335
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An efficient synthesis of 2-aminopyrroles from enaminone–amidine adduct
and phenacyl/benzyl/heteroalkyl-halides
Hitesh B. Jalani, Amit N. Pandya, Arshi B. Baraiya, Jitendra C. Kaila, Dhaivat H. Pandya, Jayesh A. Sharma,
⇑
V. Sudarsanam, Kamala K. Vasu
Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054,
Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report an efficient and facile synthesis of substituted 2-aminopyrroles from the reaction of
enaminone–amidine adduct and various phenacyl, benzyl, or heteroalkyl halides in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in good to excellent yields. The reaction proceeds through
an intramolecular 5-exo trig cyclization resulting into diversely substituted 2-aminopyrroles.
Ó 2011 Published by Elsevier Ltd.
Received 25 June 2011
Revised 23 August 2011
Accepted 25 August 2011
Available online 1 September 2011
Keywords:
2-Aminopyrroles
Enaminone
Cyanamide
5-Exo trig
N-alkylation
Many natural and biologically active compounds like hemes,
bile pigments, chlorophyll etc. have pyrrole as the basic scaffold
which is also present in pharmaceuticals1 and compounds of mate-
rial sciences.2 2-Aminopyrroles are part of many different bioactive
compounds with reported bioactivities like, IL-6 production inhibi-
tion, IkB kinase-b inhibition, intergrin antagonists, signals trans-
duction modulators, antitumor, and antibacterial agents3 are a
few of them. Despite the large number of methods for the synthesis
of pyrroles reported so far, it is still challenging to prepare
2-aminopyrroles with various substituents directly from readily
available building blocks. Several methods were reported for the
synthesis of 2-aminopyrroles by Domling,4 Zhu,5 Nair6 and Shaa-
bani7 using multi-component reactions of acidic nitriles or isocya-
nides as starting materials. 2-Aminopyrroles are not readily
available precursors; in general, such species are difficult to make
and are notoriously prone to decomposition if the adjacent carbon
attached to the carbon of the amino group is not bearing the elec-
tron withdrawing groups. To the best of our knowledge, there are
no simple and convenient methods for the synthesis of substituted
2-aminopyrroles using the readily available and simple starting
materials like enaminone–amidine adduct and phenacyl/benzyl/
hetero-alkyl halides.
concerned, they can react with both electrophiles as well as nucle-
ophiles.9,10 It is known that the electron rich double bond of enami-
no-ketones has stronger tendency to react as a nucleophile toward
the electron deficient species. The existing methods for the synthe-
sis of pyrroles from enamines and carbonyl compounds are facili-
tated by oxidizing agents for cyclization and results in pyrroles
without amine function.11
The focus of our group is to develop new synthetic methods for
the small heterocyclic compounds particularly bearing the amino
group within the heterocycles. We have developed the synthesis
of 2-aminothiophene,12 2-aminothiazole13 and 2-aminoimidaz-
ole14 using different adducts of isothiocyanates with enamines or
amidines. We have been working on the reaction of enamines/
enaminones with different isothiocyanates to produce the enami-
none–isothiocyanate adducts which are useful intermediates for
the synthesis of substituted 2-aminothiophenes.15 Herein, our
interest was to check the reactions of enaminones with various
electrophiles, in particular their reactions with cyanamide to get
the enaminone–amidine adduct.
We reasoned that, we can use the nucleophilic nature of the
enaminone by reacting them with electrophilic cyanamide (car-
bodimide) in the presence of a mild acid to produce the enami-
none–amidine adduct. Further reaction of this adduct with active
methylene halides could give the desired pyrroles. Herein, we
report a novel synthesis of 2-aminopyrroles (3 and 5) by the reac-
tion of enaminone–amidine adduct 1 with various phenacyl
bromides 2, benzyl and heteroalkyl halides 4 in the presence of
DBU in good to excellent yield (Scheme 1).
Enaminones (enamines) are versatile and readily available inter-
mediates and their chemistry has received considerable attention
in recent years.8 As far as the chemical reactivity of enamines is
⇑
Corresponding author. Tel.: +91 79 27439375; fax: +91 79 27450449.
E-mail addresses: kamalav@perdcentre.com, kamkva@gmail.com (K.K. Vasu).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.08.149

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H. B. Jalani et al. / Tetrahedron Letters 52 (2011) 6331–6335
Scheme 1. Synthesis of 5-ketoaryl and 5-aryl-2-aminopyrroles.
From the above reaction mechanism, one can rule out the pos-
sibility of the attack of the amino group of cyanamide on the car-
bonyl carbon of enaminone, because cyanamide is already in
protonated form due to the presence of mild p-toluene sulfonic
acid and hence behave predominantly as an electrophile.
Under the developed conditions for the synthesis of enaminone–
amidine adduct 1, we synthesized this adduct in multigram scale.
The second step is the reaction of enaminone–amidine adducts with
various phenacyl, benzyl, or heteroalkyl halides in the presence of
DBU to give substituted 2-aminopyrroles. The reactions of the
enaminone–amidine adduct 1 with different phenacyl bromides
(2a–h) in the presence of DBU resulted in 5-ketoaryl-2-aminopyr-
roles (3a–h) in good to excellent yield. Further to check the effi-
ciency of the base, we selected various bases to optimize the
reaction conditions by selecting the reaction of 1 with 4-chlorophe-
nacyl bromide 2a for the survey. The representative results are sum-
marized in Table 1. The results are clearly indicating that as
compared to other bases, DBU should be selected for the cyclization
reaction of pyrroles, because optimum yield and shorter reaction
time was achieved when DBU was used as a base. Once the opti-
mized protocol in hand, we turned to demonstrate the generality
of this protocol using various benzyl halides (4a–e) and hetero alkyl
halides (4f–h) in order to get 5-aryl and 5-heteroaryl-2-aminopyr-
roles (5a–h). The reaction with electron withdrawing groups pres-
ent in the aromatic ring of phenacyl bromides resulted in excellent
yield while the reaction of the electron releasing groups were
observed with comparatively lower yields.
The reactions of enaminone–amidine adduct 1 with aromatic
alkyl halides in the presence of DBU resulted in 2-aminopyrroles
with aryl substitution at 5th position of the pyrrole scaffold with
reasonably good yields (Table 2, 5a–e) suggesting the reactivity
of enamine–amidine adduct toward the benzyl halide.19 This has
provided us a platform for testing the reactivity of the adduct 1
with heterocyclic alkyl halides 4 to get the 2-aminopyrrole with
heterocyclic substitution at 5th position of pyrroles (Table 2, entry
5f–h).20
Scheme 2. Plausible reaction mechanism for enaminone–amidine adduct
formation.
The first step of the reaction sequence starts with the reaction of
enamino-ketone 8 with cyanamide 6 in the presence of mild acid
(p-toluene sulfonic acid) in tetrahydrofuran (THF) at room temper-
ature. After stirring for 3–4 h, a white solid was observed in the
flask as enaminone–amidine adducts 1 (Ref. 16). The feasibility of
this reaction may be attributed to the increased nucleophilic char-
acter of the double bond of enamino-ketone toward the electro-
philic cyanamide facilitated by the lone pair of electrons of the
pyrrolidine nitrogen atom. The protonation by PTS to the nitrogen
atom of the cyano group increases electrophilic nature of the cyan-
amide carbon and hence allows the double bond to attack. This
reaction may proceed similarly to that of the enamines with iso-
thiocyanates for the preparation of adducts as mentioned in the lit-
erature.13,14 The plausible reaction mechanism for the enaminone–
amidine formation (Scheme 2), in which the cyanamide is proton-
ated with the help of PTS to give species 7, this carbocation bearing
the electron deficient central carbon atom is further attacked by
the double bond of nucleophilic enamino-ketone 8 to produce
the species 9. This intermediate further transforms to enami-
none–amidine adduct 1.
Table 1
Optimization of reaction parameters for 2-aminopyrrole synthesis
O
Cl
Cl
N
O
Base
THF+ACN
NH2
3a
+
N
H
Br
2a
O
O
HN NH2
1
Sr. No.
Base
Base (equiv)
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
DBU
Pyridine
Potassium tertiary butoxide
Triethylamine
Potassium carbonate
1.0
1.0
1.0
1.0
1.0
25
25
25
25
25
2
12
9
10
16
89
51
49
42
38
a
Yields refer to chromatography pure product.

H. B. Jalani et al. / Tetrahedron Letters 52 (2011) 6331–6335
6333
Table 2
Substituted 5-ketoaryl and 5-aryl/heteroaryl-2-aminopyrroles
Sr. No.
Enamino-ketone 1
Structure of compounds 2 and 4
Products 3 and 5
Yielda (%)
Cl
O
N
O
Cl
Br
1
89
71
69
70
68
88
86
83
NH2
3a
2a
O
N
H
O
O
HN NH2
N
O
Br
2
3
4
5
6
7
8
2b
O
NH2
3b
N
H
O
HN NH2
O
O
N
O
O
Br
Br
NH2
3c
2c
O
N
H
HN NH2
O
O
S
O
O
O
S
O
N
O
NH2
3d
N
H
2d
O
O
HN NH2
O
O
N
O
Br
2e
NH2
3e
N
H
HN NH2
O
Br
O
N
O
Br
Br
Br
NH2
3f
2f
O
N
H
HN NH2
O
O
O
Cl
Cl
O
N
O
Cl
NH2
3g
2g
O
O
N
H
HN NH2
Cl
O
O
O
N
O
HN
HN
NH2
3h
N
H
Br
HN NH2
2h
O2N
O
N
O
Br
9
79
76
78
NH2
5a
4a
N
H
HN NH2
O2N
NC
NC
O
N
O
Br
10
NH2
5b
4b
N
H
HN NH2
NO2
O
N
O
Br
11
12
NH2
5c
4c
4d
N
H
HN NH2
NO2
O
Br
N
O
62
NH2
5d
N
H
HN NH2
(continued on next page)

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H. B. Jalani et al. / Tetrahedron Letters 52 (2011) 6331–6335
Table 2 (continued)
Sr. No.
Enamino-ketone 1
Structure of compounds 2 and 4
Products 3 and 5
Yielda (%)
Cl
O
N
O
Br
4e
13
68
NH2
5e
N
H
HN NH2
Cl
Cl
O
N
O
N
14
15
65
67
Cl
NH2
5f
Cl
N
N
H
4f
HN NH2
CF3
O
O
N
O
CF3
O
NH2
5g
Cl
N
N
H
HN NH2
4g
O
N
O
N
O
NH
Br
NH2
5h
N
N
16
61
N
H
4h
HN NH2
NH
O
a
Yields refer to isolated products by column chromatography.
in the case of benzyl halide/hetero alkyl halide instead of phenacyl
halide resulting in 5-aryl/heteroaryl-2-aminopyrroles (5a–h).17
In conclusion, we have developed a novel synthesis of 5-substi-
tuted-2-aminopyrrole using enaminone–amidine adduct with
phenacyl bromides, benzyl halides, and hetero alkyl halides
through an intramolecular 5-exo trig cyclization in good to excel-
lent yields. The advantage of this method is its mild conditions
and the product can be isolated with good purity. This approach
could be useful for the generation of compound libraries of pyr-
roles scaffold with diverse substitutions for biological screenings.
The mild reaction condition of the present process makes it an
interesting approach. Furthermore the presence of an amino group
in the pyrroles makes them biologically important synthetic inter-
mediates for the synthesis of further nitrogen containing other het-
erocyclic compounds.
Scheme 3. Mechanistic rationale for 2-aminopyrrole synthesis.
Acknowledgments
Thus, in
a representative experiment, enaminone–amidine
adduct 1 and 4-chlorophenacyl bromide 2a were reacted in a mix-
ture of solvent THF/ACN (1:1) at room temperature in the presence
of DBU for 2–3 h. The progress of the reaction was monitored by
TLC. The structure of the compound was assigned with the help
of 1H NMR, 13C NMR and Mass spectrometry.18
A plausible reaction mechanism is shown in the Scheme 3. The
reaction of enaminone–amidine adduct 1 with phenacyl bromide 2
in which the nucleophilic double bond of adduct attacks the acidic
methylene group due to the N-alkylation to give the intermediate
10. In the next step, an acidic proton of the methylene group is
abstracted by the base to produce carbanion 11. The most impor-
tant step of this new method is the cyclization, which occurs
We gratefully acknowledge the financial support for this work
from B.V. Patel PERD centre. We thank Professor H. Padh and C.J.
Shishoo, Directors of B.V. Patel PERD centre, for their constant
encouragement and support. H.B.J. thanks PERD Centre for the doc-
toral fellowship and Hemant Gadpe (Cadila Pharmaceuticals) for
NMR analysis.
References and notes
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between the newly generated carbanion at the
a-position of the
carbonyl group and an imine carbon to which the electron pulling
quaternary nitrogen is attached. This carbanion then attacks the
electrophilic imine carbon of enaminone to produce an intramolec-
ular 5-exo trig cyclization to 12 followed by elimination of the
pyrrolidine resulting into the formation of 5-ketoaryl-2-aminopyr-
roles (3a–h). A similar selective cyclization to produce imidazoles
by the reaction of guanidines with phenacyl bromides have already
been reported in the literature.14 The same mechanism is followed
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10. (a) Missio, L. J.; Braibante, H. S.; Braibante, M. E. F. J. Heterocycl. Chem. 1996, 37,
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12. Pillai, A. D.; Rathod, P. D.; Franklin, P. X.; Padh, H.; Vasu, K. K.; Sudarsanam, V.
Bioorg. Med. Chem. 2005, 13, 6685.
13. (a) Franklin, P. X.; Pillai, A. D.; Rathod, P. D.; Yerande, S.; Nivsarkar, M.; Padh,
H.; Vasu, K. K.; Sudarsanam, V. Eur. J. Med. Chem. 2008, 43, 129.
14. (a) Kaila, J. C.; Baraiya, A. B.; Pandya, A. N.; Jalani, H. B.; Vasu, K. K.;
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Vasu, K. K.; Sudarsanam, V. Tetrahedron Lett. 2008, 49, 7220.
17. General procedure for the synthesis of 2-aminopyrroles (3 and 5): To a stirred
suspension of enaminone–amidine adduct (4.0 mmol) in a solvent mixture of
ACN + THF (1:1) (30 mL), DBU (6.0 mmol) was added slowly at room
temperature. Clear solution was observed. Then
a solution of phenacyl
bromide or benzyl halide or hetero alkyl halide (4.0 mmol) in 10 mL of THF
was added within half an hour. Progress of the reaction was monitored by TLC
using ethyl acetate/hexane (2:8). The reaction was then allowed to maintain
for 2–3 h. After completion of reaction, silica gel was added to the reaction
mixture and concentrated on rotavapor. The material was purified by column
chromatography using ethyl acetate/methanol (85:15) as eluting phase.
18. Analytical data of 1-(2-amino-5-(4-chlorobenzoyl)-4-methyl-1H-pyrrol-3-yl)
ethanone (3a).Chemical formula: C14H13ClN2O2; light gray solid; yield: 89%;
mp: 142–144 °C; 1H NMR (300 MHz, DMSO-d6): d = 8.09–8.06 (d, J = 8.7 Hz,
2H), 7.68–7.65 (d, J = 8.7 Hz, 2H), 6.35 (s, 1H, NH), 5.44 (s, 2H, NH2), 2.24 (s, 3H),
2.229 (s, 3H); 13C NMR (300 MHz, DMSO-d6): d = 192.3, 174.6, 159.6, 158.1,
156.1, 139.0, 133.1, 130.0, 129.0, 105.3, 24.6, 19.6; mol. wt: 276.72; Found
(LCMS): 277.8 and 278.8.
15. Jalani, H. B.; Kaila, J. C.; Baraiya, A. B.; Pandya, A. N.; Vasu, K. K.; Sudarsanam, V.
Tetrahedron Lett. 2010, 51, 5686.
16. General procedure for the synthesis of enaminone–amidine adduct (1): To a stirred
solution of cyanamide (6.0 mmol) in THF (50 mL), para toluene sulphonic acid
(0.3 mmol) was added and allowed to stir for half an hour at room
19. Analytical
data
of
1-(2-amino-4-methyl-5-(4-nitrophenyl)-1H-pyrrol-3-
yl)ethanone (5a). Chemical formula: C13H13N3O3; buff solid; yield: 79%; mp:
205–208 °C; 1H NMR (300 MHz, DMSO-d6): d = 8.22–8.19 (d, J = 8.7 Hz, 2H),
7.42–7.39 (d, J = 8.7 Hz, 2H), 6.36 (s, 1H, NH), 5.32 (s, 2H, NH2), 2.25 (s, 3H), 2.25
(s, 3H); 13C NMR (300 MHz, DMSO-d6): d = 174.6, 157.7, 156.4, 146.7, 144.2,
133.6, 127.6, 123.8, 105.7, 24.6, 19.5; mol. wt: 259.26; Found (LCMS): 260.4.
20. Analytical data of 1-(2-amino-5-(6-chloropyridin-2-yl)-4-methyl-1H-pyrrol-3-yl)
ethanone (5f). Chemical formula: C12H12ClN3O; pinkish gray solid; yield: 65%;
mp: 97–100 °C; 1H NMR (300 MHz, DMSO-d6): d = 8.33–8.32 (d, J = 2.4 Hz, 1H),
7.68–7.65 (m, 1H), 7.49–7.46 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H, NH), 5.19 (s, 2H,
NH2), 2.32 (s, 3H), 2.22 (s, 3H); 13C NMR (300 MHz, DMSO-d6): d = 174.4, 159.6,
157.9, 156.3, 149.2, 148.6, 138.3, 131.8, 124.3, 105.8, 24.6, 19.6; mol. wt:
249.70; Found (LCMS): 250.7.
temperature. To this,
a solution of enamino-ketone (6.0 mmol) in THF
(10 mL) was added within half an hour. The reaction was allowed to stir for
3–4 h and the progress of reaction was monitored by TLC (ethyl acetate/hexane
2:8). The completion of reaction was indicated by the formation of white solid.
This solid was then filtered and washed with hexane (2 Â 10 mL). This solid
was air dried and used for the next step. Chemical formula: C10H17N3O; off
white solid; Yield: 59%; mp: 184–186 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.15 (s, 3H, CH3), 2.16 (s, 3H, CH3), 3.32 (t, 2H, CH2), 3.47 (t, 2H, CH2), 5.42 (s,
2H, NH2), 11.65 (s, 1H, NH); 13C NMR (300 MHz, DMSO-d6): d = 19.9, 28.7, 29.3,
47.7, 96.2, 157.1, 159.7, 196.8; mol. wt: 195.26; Found (LCMS): 196.1.