Synthesis of 2,3,4,5-tetrasubstituted pyrroles and 1,4-dihydro-tetraarylpyrazines using acidic alumina as a heterogeneous catalyst

Article abstract of DOI:10.1007/s13738-016-0912-0

Abstract: Some new 2,3,4,5-tetrasubstituted pyrroles were synthesized via three-component condensation reaction of benzoin derivatives, 1,3-dicarbonyl compounds, and ammonium acetate using acidic Al₂O₃ as an efficient and reusable he

Full text of DOI:10.1007/s13738-016-0912-0

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0912-0
ORIGINAL PAPER
Synthesis of 2,3,4,5‑tetrasubstituted pyrroles
and 1,4‑dihydro‑tetraarylpyrazines using acidic alumina as a
heterogeneous catalyst
Khodabakhsh Niknam1 · Hashem Sharghi2 · Mohsen Khataminejad1
Received: 31 January 2016 / Accepted: 10 June 2016
© Iranian Chemical Society 2016
Abstract Some new 2,3,4,5-tetrasubstituted pyrroles were
synthesized via three-component condensation reaction
of benzoin derivatives, 1,3-dicarbonyl compounds, and
ammonium acetate using acidic Al2O3 as an efficient and
reusable heterogeneous catalyst in refluxing ethanol in high
yields. Also, acidic alumina was catalyzed 1,4-dihydro-
tetraarylpyrazines by the condensation reaction of benzoins
and ammonium acetate in refluxing ethanol in high yields.
Alumina showed much the same efficiency when used in
consecutive reaction runs.
Introduction
Pyrroles are prominent in pharmaceuticals and repre-
sent an important class of heterocyclic compounds [1–4].
They are commonly found as structural motifs in natural
(storniamide A, halitulin, oroidin, lamellarin P, sceptrin,
marinopyrrole B, and atorvastatin) and synthetic products
[4, 5] (Fig. 1). Polyfunctionalized pyrroles have attracted
particular attention in drug discovery due to their various
pharmacological properties [4] such as antibacterials [6],
antitumorals, as well as antifungal [7], anti-inflammatory
[8], antioxidant [9], and central nervous system agents [4].
A variety of classical methods have been reported for
the synthesis of pyrroles, such as the Barton–Zard [10],
Graphical Abstract Acidic alumina was used as hetero-
geneous acidic catalyst for the synthesis of tetrasubstituted
pyrroles in refluxing ethanol. The catalyst could be recy-
cled for several times.
O
R1
Ar
Ar
O
Ar
Ar
R1
O
O
Acidic alumina
Ethanol/ Reflux
+
+
NH4OAc
OH
R
N
H
R
Ar = C6H5-, 4-Me-C6H4-, 4-F-C6H4-, 4-Cl-C6H4-
Keywords Acidic alumina · Pyrroles · 1 · 4-Dihydro-
tetraarylpyrazines · Synthesis · Heterogeneous catalyst
Hantzsch [11], Knorr [12, 13], Trofimov [14], Paal–Knorr
[15, 16], and Clauson–Kaas [17–19] reactions and their
modifications. In addition, pyrroles have also been syn-
thesized by the Huisgen reaction [20–22], cyclization of
N-propargylic derivatives [23, 24], including propargyl
aziridines [25, 26], through the cyclocondensation of vinyl
azides with 1,3-dicarbonyls [27, 28], transition-metal-cat-
alyzed cyclization [29], [3 + 2] cycloadditions [30], and
multi-component reactions [4, 31–39], among various other
alternatives. Nevertheless, some of these methods need
multiple steps, expensive or prefunctionalized substrates,
and using reagents which generate halide wastes. With
* Khodabakhsh Niknam
niknam@pgu.ac.ir
1
Department of Chemistry, Faculty of Sciences, Persian Gulf
University, Bushehr 75169, Iran
2
Chemistry Department, College of Science, Shiraz
University, Shiraz 71454, Iran
1 3

J IRAN CHEM SOC
HO
OH
NH2
OH
O
HO
HO
N
HN
Br
N
N
H
NH
NH
Br
Br
N
NH2
NH
NH2
H
N
N
NH
Br
N
NH
O
N
H
O
Me
Halitulin
Sceptrin
Oroidin
Fig. 1 Some polysubstituted pyrrole-containing bioactive natural product
respect to green chemistry, the development of methods
with starting from inexpensive and easily available sub-
strates remains a demanding goal.
General procedure for the synthesis of 2,3,4,5‑tetrasub‑
stituted pyrroles
Alumina, silica gel, zeolites, and clays are the most
important class of solids which have been used for surface
organic chemistry [40–47]. Among them, acidic alumina
that commonly used for column chromatography certainly
has one of the most interesting of these surface properties,
which suggests a very rich organic chemistry may occur
there.
We report here the synthesis of 2,3,4,5-tetrasubsti-
tuted pyrroles via three-component condensation reac-
tion of benzoins, 1,3-dicarbonyl compounds, and ammo-
nium acetate using acidic alumina as catalyst in refluxing
ethanol.
To a mixture of benzoin derivative (1 mmol), 1,3-dicar-
bonyl compound (1 mmol) and NH4OAc (1.5 mmol)
in ethanol (3 mL) were added acidic alumina (0.04 g,
0.04 mol %), and the mixture was refluxed for appropria-
tive times (Table 2). After completion of the reaction (as
indicated by thin-layer chromatography), warm ethanol
(3 × 5 mL) was added and the catalyst was separated by
filtration. The filtrated was cooled to room temperature
and precipitated was filtered. For further purification, the
precipitates were recrystallized from ethanol to give cor-
responding product. The products 1d, 1i, 1j, and 1 k were
purified by silica gel column chromatography employing
n-hexane/ethyl acetate as the eluent.
Experimental
1‑(2‑Methyl‑4,5‑di‑p‑tolyl‑1H‑pyrrole‑3‑yl)‑ethanone
(1a) (Table 2, entry 1)
Chemicals and reagents
White solid, recrystallized from ethanol, mp 237–238 °C
(Lit. [34] 237–238). IR (KBr): 3286.5 (N–H), 1604.7
(cm−1) (N–C=O). 1H-NMR (400 MHz, DMSO-d6): δ
(ppm) 1.74 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.34 (s, 3H,
CH3), 2.46 (s, 3H, CH3), 6.99–7.05 (m, 4H, Ar), 7.09 (d,
2H, J = 7.6 Hz, Ar), 7.17 (d, 2H, J = 8.0 Hz, Ar), 11.52 (s,
1H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 13.8,
20.6, 20.8, 30.5, 121.5, 122.0, 126.4, 126.5, 128.7, 128.9,
129.4, 130.6, 134.0, 134.8, 135.3, 135.7, 194.5.
Chemicals were purchased from Merck and Aldrich
chemical companies. The products were characterized by
comparison of their spectral and physical data with those
1
reported in the literature. For the recorded H-NMR spec-
tra, we used Bruker Ultrashield (400 MHz) in pure deuter-
ated CDCl3 or DMSO-d6 solvent with tetramethylsilane
(TMS) as internal standards. Mass spectra were recorded
on a FINNIGAN-MAT 8430 mass spectrometer operating
at 70 eV. FTIR spectroscopy (Shimadzu FTIR-8300 spec-
trophotometer) was employed for characterization of the
products. Melting points were determined in open capil-
lary tubes in a Barnstead Electrothermal 9100 BZ circulat-
ing oil melting point apparatus. The reaction monitoring
was accomplished by TLC on silica gel PolyGram SIL G/
UV254 plates. Column chromatography was carried out on
columns of silica gel 60 (70–230 mesh). Acidic alumina
was purchased from Merck (Aluminum oxide 90 active
acidic (0.063–0.2 mm).
2‑Methyl‑4,5‑di‑p‑tolyl‑1H‑pyrrole‑3‑carboxylic acid
methyl ester (1b) (Table 2, entry 2)
White solid, recrystallized from ethanol, 90 % yield; mp
175–176 °C. IR (KBr): 3317.3 (N–H), 1681.8 (cm−1) (N–
1
C=O). H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.21 (s,
3H, CH3), 2.30 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.47 (s,
3H, OCH3), 6.97–7.07 (m, 8H, Ar), 11.47 (s, 1H, NH).
13C NMR (100 MHz; CDCl3) δ (ppm): 13.3, 20.6, 20.8,
1 3

J IRAN CHEM SOC
50.0, 111.0, 121.9, 126.7, 127.1, 128.1, 128.7, 129.4,
130.4, 133.3, 134.8, 135.3, 135.3, 165.1. MS (EI, 70 eV):
m/z (%): 320 (M+ + 1, 22.6), 319 (M+, 45.9), 244 (17.4),
149 (52.2), 83 (base peak). Anal. Calcd for C21H21NO2:
C, 78.97; H, 6.63; N, 4.39; found: C, 78.74; H, 6.67, N,
4.21.
2‑Methyl‑4,5‑diphenyl‑1H‑pyrrole‑3‑carboxylic acid
ethyl ester (1f) (Table 2, entry 6)
White solid, recrystallized from ethanol, mp 203–204 °C
(Lit. [34] 206–208). IR (KBr): 3320.5 (N–H), 1682.0
1
(cm−1) (N–C=O). H-NMR (400 MHz, CDCl3): δ (ppm)
0.93 (t, 3H, J = 7.1 Hz, CH3), 2.51 (s, 3H, CH3), 3.97 (q,
2H, J = 7.1 Hz, OCH2), 7.00–7.21 (m, 10H, Ar), 8.26 (s,
1H, NH). 13C-NMR (100 MHz, CDCl3): δ (ppm) 12.8,
12.9, 58.2, 111.6, 122.4, 125.3, 125.5, 125.7, 126.2, 126.6,
127.5, 129.7, 131.1, 134.4, 135.0, 164.6.
2‑Methyl‑4,5‑di‑p‑tolyl‑1H‑pyrrole‑3‑carboxylic acid
benzyl ester (1c) (Table 2, entry 3)
White solid; recystalized from ethanol, 89 % yield; mp
171–172 °C. IR (KBr): 3309.6 (N–H), 1678.1 (cm−1
)
1
(N–C=O). H NMR (400 MHz, CDCl3) δ (ppm): 2.18
(s, 3H, CH3), 2.25 (s, 3H, CH3), 2.48 (s, 3H, CH3),
5.01 (s, 2H, OCH2), 6.91–6.97 (m, 8H, Ar), 7.03–7.06
(m, 2H, Ar), 7.12–7.17 (m, 3H, Ar), 8.31 (s, 1H, NH).
13C NMR (100 MHz, CDCl3) δ (ppm): 13.0, 20.1, 20.3,
64.2, 111.1, 121.8, 125.6, 126.4, 126.4, 126.7, 127.9,
128.1, 128.3, 128.7, 129.5, 132.0, 134.6, 134.7, 135.2,
135.4, 164.5. MS (EI, 70 eV): m/z (%) = 396 (M+ + 1,
12.1), 395 (M+, 38.1), 305 (18.1), 304 (base peak), 262
(5.1), 244 (5.2), 91 (11.5). Anal. Calcd for C27H25NO2:
C, 82.00; H, 6.37; N, 3.54; found: C, 81.76; H, 6.39; N,
3.36.
2‑Methyl‑4,5‑diphenyl‑1H‑pyrrole‑3‑carboxylic acid
methyl ester (1g) (Table 2, entry 7)
White solid, recrystallized from ethanol, mp 183–184 °C
(Lit. [34] 178–180). IR (KBr): 3313.1(N–H), 1680.0
1
(cm−1) (N–C=O). H-NMR (400 MHz, CDCl3): δ (ppm)
2.62 (s, 3H, CH3), 3.62 (s, 3H, OCH3), 7.11–7.26 (m, 10H,
Ar), 8.29 (s, 1H, NH). 13C-NMR (100 MHz, CDCl3): δ
(ppm) 15.1, 51.7, 113.3, 124.5, 127.5, 127.7, 128.1, 128.8,
129.6, 131.9, 132.2, 133.3, 136.9, 137.1, 167.1.
2‑Methyl‑4,5‑diphenyl‑1H‑pyrrole‑3‑carboxylic acid
benzyl ester (1h) (Table 2, entry 8)
1‑(2‑Methyl‑4,5‑di‑p‑tolyl‑1H‑pyrrole‑3‑yl)‑phe‑
nyl‑methanone (1d) (Table 2, entry 4)
White solid; recystalized from ethanol, 89 % yield; mp
204–205 °C. IR (KBr): 3309.0 (N–H), 1679.0 (cm−1) (N–
C=O). H NMR (400 MHz, CDCl3) δ (ppm): 2.50 (s, 3H,
1
Yellow solid, purified by column chromatography on sil-
ica gel, mp 220–221 °C. IR (KBr): 3309.6 (N–H), 1620.1
(cm−1) (N–C=O). 1H-NMR (400 MHz, DMSO-d6) δ
(ppm): 2.16 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 6.82–7.52 (m, 13H, Ar), 11.53 (s, 1H, NH). 13C-
NMR (100 MHz, DMSO-d6) δ (ppm): 12.7, 20.6, 120.9,
121.5, 126.8, 127.0, 127.8, 128.2, 128.8, 129.4, 130.0,
131.3, 132.6, 133.4, 134.4, 135.5, 139.8, 192.8. MS: m/z
(%):366 (M+ + 1, 10.8), 365 (M+, 34.8), 279 (17.4),
167 (30.4), 149 (base peak), 57 (80.7). Anal. Calcd for
C26H23NO: C, 85.45; H, 6.34; N, 3.83; found: C, 85.18; H,
6.38; N, 3.61.
CH3), 5.00 (s, 2H, OCH2), 6.91–6.93 (m, 2H, Ar), 6.98–
7.00 (m, 2H, Ar), 7.04–7.09 (m, 3H, Ar), 7.11–7.16 (m,
8H, Ar), 8.31 (s, 1H, NH). 13C NMR (100 MHz; CDCl3)
δ (ppm): 13.0, 64.2, 111.2, 122.3, 125.4, 125.5, 125.7,
126.4, 126.5, 126.7, 126.7, 127.2, 127.4, 129.8, 131.1,
134.9, 135.0, 135.3, 164.4. MS (EI, 70 eV): m/z (%) = 369
(M+ + 2, 3.3), 368 (M+ + 1, 20.0), 367 (M+, base peak),
366 (17.5), 338 (8.3), 322 (10.1), 265 (17.5), 105 (11.6),
77 (5.1). Anal. Calcd for C25H21NO2: C, 81.72; H, 5.76; N,
3.81; found: C, 81.47; H, 5.81; N, 3.52.
2‑Methyl‑4,5‑diphenyl‑1H‑pyrrole‑3‑yl)‑phenyl‑metha‑
none (1i) (Table 2, entry 9).
2‑Methyl‑4,5‑diphenyl‑1H‑pyrrole‑3‑yl)‑ethanone (1e)
(Table 2, entry 5)
Yellow solid, purified by column chromatography on silica
gel, mp 218–219 °C (Lit. [34] 223–225). IR (KBr): 3286.5
(N–H), 1604.7 (cm−1) (N–C=O). 1H-NMR (400 MHz,
DMSO-d6): δ (ppm) 2.26 (s, 3 H, CH3), 6.95–7.37 (m, 15
H, Ar), 11.65 (s, 1 H, NH). 13C-NMR (100 MHz, DMSO-
d6): δ (ppm) 12.7, 121.0, 122.0, 125.7, 126.3, 126.8, 127.1,
127.6, 127.8, 128.9, 129.6, 130.2, 131.3, 132.2, 134.0,
135.6, 139.7, 192.8.
White solid, recrystallized from ethanol, mp 168–170 °C
(Lit. [32] 170–172 °C). IR (KBr): 3197.0 (N–H), 1622.0
1
(cm−1) (N–C=O). H-NMR (400 MHz, CDCl3): δ (ppm)
1.92 (s, 3H, CH3), 2.61 (s, 3H, CH3), 7.10–7.34 (m, 10H,
Ar), 8.51 (s, 1H, NH). 13C-NMR (100 MHz, CDCl3): δ
(ppm) 15.2, 31.8, 123.5, 123.5, 127.1, 127.8, 128.0, 128.2,
129.1, 129.3, 131.9, 133.5, 137.0, 138.1, 197.6.
1 3

J IRAN CHEM SOC
1‑[4,5‑Bis(4‑fluorophenyl)‑2‑methyl‑1H‑pyrrol‑3yl]‑eth‑
anone (1j) (Table 2, entry 10).
General procedure for the synthesis of 1,4‑dihydro‑tet‑
rasubstituted pyrazines
Yellow solid, purified by column chromatography on silica
gel, 90 % yield; mp 239–240. IR (KBr): 3326.0 (N–H),
1621.0 (cm−1) (N–C=O). 1H NMR (400 MHz, DMSO-d6)
δ (ppm): 1.81 (s, 3H, CH3), 2.49 (s, 3H, CH3), 7.08–7.24
(m, 8H, Ar), 11.67 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 13.8, 30.5, 115.0, 115.3, 120.8, 121.9,
126.0, 128.6, 128.7, 132.6, 132.6, 135.2, 194.1. MS (EI,
70 eV): m/z (%) = 313 (M+ + 2, 2.7), 312 (M+ + 1, 26.4),
311 (M+, 93.6), 310 (15.5), 297 (35.5), 296 (base peak),
281 (15.5), 266 (17.3), 253 (29.1), 95 (5.5). Anal. Calcd for
C19H15F2NO: C, 73.30; H, 4.86; F, 12.20; N, 4.50; found:
C, 73.06; H, 4.88; N, 4.32.
To a mixture of benzoin derivative (2 mmol), NH4OAc
(3 mmol) in ethanol (3 mL) was added acidic alumina
(0.05 g, 0.05 mol %), and the mixture was refluxed for
appropriative times (Table 3). After completion of the reac-
tion (as indicated by thin-layer chromatography), warm
ethanol (3 × 5 mL) was added and the catalyst was sepa-
rated by filtration. The filtrated was cooled to room temper-
ature and precipitated was filtered. For further purification,
the precipitates were recrystallized from ethanol to give
corresponding product.
2,3,5,6‑Tetraphenyl‑1,4‑dihydro‑pyrazine (2a) (Table 3,
entry 1)
1‑[4,5‑Bis‑(4‑fluoro‑phenyl)‑2‑methyl‑1H‑pyrrole‑3‑car‑
boxylic acid methyl ester (1k) (Table 2, entry 11)
White solid; recystalized from ethanol, 70 % yield; mp
>255 °C (Lit. [48] 265 °C). IR (KBr): 3193.9 (N–H),
1610.0 (cm−1) (C=C). 1H NMR (400 MHz, CDCl3)
δ (ppm): 7.21–7.56 (m, 16H, Ar), 8.08–8.10 (d, 4H,
J = 7.2 Hz, Ar), 12.69 (s, 2H, NH). 13C NMR (100 MHz,
CDCl3) δ (ppm): 129.2, 129.6, 130.5, 138.9, 149.2. MS (EI,
70 eV): m/z (%) = 386 (M+, 1.3), 385 (8.9), 384 (19.4),
383 (18.9), 298 (10.6), 297 (51.9), 296 (base peak), 295
(57.7), 178 (12.8), 165 (69.2), 97 (19.4), 89 (30.6), 83
(45.1), 71 (35.7), 57 (88.0).
Yellow solid, purified by column chromatography on silica
gel, mp 211–213 °C (Lit. [38] 215–218). IR (KBr): 3287.0
(N–H), 1678.0 (cm−1) (N–C=O). 1H-NMR (400 MHz,
DMSO-d6) δ (ppm): 2.49 (s, 3H, CH3), 3.50 (s, 3H, OCH3),
7.08–7.15 (m, 8H, Ar), 11.64 (s, 1H, NH). 13C-NMR
(100 MHz, DMSO-d6) δ (ppm): 13.3, 50.1, 114.3, 115.0,
115.3, 115.5, 115.5, 127.2, 127.3, 128.8, 128.9, 132.2
(1JC–F = 120.0 Hz), 132.4, 135.8, 164.9. MS: m/z (%): 329
(M+ + 2, 3.6), 328 (M+ + 1, 35.5), 327 (M+, base peak),
312 (55.5), 296 (49.1), 266 (69.1), 253 (16.3), 95 (5.5).
2,3,5,6‑Tetra‑(4‑methoxyphenyl)‑1,4‑dihydro‑pyrazine
(2b) (Table 3, entry 2)
1‑[4,5‑Bis‑(4‑chloro‑phenyl)‑2‑methyl‑1H‑pyr‑
role‑3‑yl]‑ethanone (1l) (Table 2, entry 12).
White solid; recystalized from ethanol, 70 % yield;
mp >255 °C. IR (KBr): 3448.5 (N–H), 1604.7 (cm−1
)
1
White solid, recrystallized from ethanol, mp 230–232 °C
(Lit. [32] 234–235 °C). IR (KBr): 3318.0 (N–H), 1619.0
(C=C). H NMR (400 MHz, DMSO-d6) δ (ppm): 3.73 (s,
12H, OCH3), 6.88 (d, 8H, J = 5.9 Hz, Ar), 7.44 (d, 8H,
J = 5.9 Hz, Ar). 13C NMR (100 MHz, DMSO-d6) δ (ppm):
56.0, 114.6, 131.4, 131.6, 147.4, 160.4. MS (EI, 70 eV):
m/z (%) = 508 (M+ + 2, 1.1), 507 (M+ + 1, 5.1), 506 (M+,
27.1), 505 (58.4), 504 (base peak), 503 (30.8), 489 (11.8),
223 (18.7), 57 (3.1). Anal. Calcd for C32H30N2O4: C, 75.87;
H, 5.97; N, 5.53; Found: C, 75.580; H, 5.62; N, 5.38.
1
(cm−1) (N–C=O). H-NMR (400 MHz, CDCl3): δ (ppm)
1.90 (s, 3H, CH3), 2.57 (s, 3H, CH3), 6.99–7.01 (m, 2H,
Ar), 7.17–7.19 (m, 4H, Ar), 7.31–7.33 (m, 2H, Ar), 8.55
(s, 1H, NH). 13C-NMR (100 MHz, CDCl3): δ (ppm) 14.8,
31.4, 122.2, 128.4, 129.2, 129.3, 130.6, 132.5, 133.1,
133.7, 135.1, 196.0.
Me
Me
O
Me
O
OH
Catalyst
O
Me
Me
+
+
NH4OAc
O
Solvent/ Conditions
N
H
Me
Me
Me
(1 mmol)
(1.5 mmol)
(1 mmol)
1a
Scheme 1 Preparation of 1-(2-methyl-4,5-di-p-tolyl-1H-pyrrole-3-yl)-ethanone
1 3

J IRAN CHEM SOC
Table 1 Investigation of the
effect of solvents and conditions
on the synthesis of pyrrole
(1a) in the presence different
amounts of some solid acids or
Lewis acids
Entry
Solvent
Catalyst loading (g)
Temperature (°C)
Time (min)
Yield (%)a
1
None
None
None
None
None
None
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
None
80
200
60
60
60
60
60
60
60
60
35
60
60
60
60
60
–
2
FeCl2 (0.04 g)
80
20
3
CuCl2 (0.04 g)
80
15
4
ZnCl2 (0.04 g)
80
40
5
SiO2-TiCl4 (0.05 g)
Acidic Al2O3 (0.04 g)
Basic Al2O3 (0.05 g)
SiO2 (0.05 g)
80
10
6
80
70
7
Reflux
Reflux
60
50
8
10
9
Acidic Al2O3 (0.04 g)
Acidic Al2O3 (0.04 g)
Acidic Al2O3 (0.04 g)
Acidic Al2O3 (0.04 g)
Acidic Al2O3 (0.04 g)
Acidic Al2O3 (0.04 g)
Acidic Al2O3 (0.04 g)
45
10
11
12
13
14
15
Reflux
rt
88
10
Reflux
Reflux
Reflux
Reflux
10
CH3CN
CHCl3
THF
60
Trace
Trace
Reaction conditions: 1,2-di-p-tolyl-ethane-1,2-dione (1 mmol), acetylacetone (1 mmol), and NH4OAc
(1.5 mmol) in solvent (3 mL)
a
Isolated yield
Table 2 Acidic alumina-catalyzed synthesis of tetrasubstituted pyrroles.
O
Acidic alumina
(0.04 g, 0.04 mol%)
R
Ar
Ar
O
Ar
Ar
R
O
O
+
+
NH4OAc
1.5 mmol
OH
Me
Ethanol/ Reflux
N
H
Me
1a-1l
1 mmol
1 mmol
Entry
1
Ar
R
Product
Time (min)
35
Yield (%)a
mp (°C)
Lit. mp (oC)
4-Me–C6H4–
Me
1a
88
237–238
237–238
[34]
2
3
4
5
4-Me–C6H4–
4-Me–C6H4–
4-Me–C6H4–
C6H5–
OMe
OCH2Ph
Ph
1b
1c
1d
1e
35
40
50
20
90
89
85
93
175–176
171–172
220–221
168–170
–
–
–
Me
170–172
[32]
6
7
C6H5–
C6H5–
OEt
1f
20
20
93
92
203–204
183–184
206–208
[34]
OMe
1g
178–180
[34]
8
C6H5–
OCH2Ph
Ph
1h
1i
35
50
20
20
20
89
90
90
92
93
204–205
218–219
239–240
211–213
230–232
–
9
C6H5–
223–225 [34]
–
10
11
12
4-F–C6H4–
4-F–C6H4–
4-Cl–C6H4–
Me
1j
1k
1l
OMe
Me
215–218 [38]
234–235
[32]
a
Isolated yield
1 3

J IRAN CHEM SOC
So, the optimized conditions were employed as fol-
lowed: benzoin derivatives (1 mmol), acetylacetone
(1 mmol), NH4OAc (1.5 mmol), and acidic alumina
(0.04 g, 0.04 mol %) in refluxing ethanol (Table 2).
O
O
Me
N
H
As shown in Table 2, it was found that 1,3-dicarbo-
nyl compounds such as acetyl acetone, benzoyl acetone,
methyl acetoacetate, ethyl acetoacetate, and benzyl ace-
toacetate reacted under optimized conditions and corre-
sponding products were obtained in high yields. In addi-
tion, it seems that benzoins bearing electron-withdrawing
groups were reacted with 1,3-dicarbonyls and ammo-
nium acetate faster than those of electron-donating ones.
This may be explained according to more positive charge
located on carbonyl group of these benzoins, which make
them more reactive toward nucleophilic attack of nitrogen
of imine intermediate [32].
Me
N
H
B
A
Expected:
H = 2.16 ppm
C = 11.7 ppm
Expected:
H = 2.55 ppm
C = 29.6 ppm
δ
δ
δ
δ
Scheme 2 Two expected regioisomers of tetrasubstituted 1H-pyr-
roles
2,3,5,6‑Tetra‑(4‑fluorophenyl)‑1,4‑dihydro‑pyrazine (2c)
(Table 3, entry 3)
To clarify mechanistic details, benzoylacetone with two
different carbonyl groups from the viewpoint of steric hin-
drance and electrophilicity was utilized in the three-com-
ponent reaction of benzoylacetone, ammonium acetate,
and benzoin, followed by NMR spectroscopy. Two enami-
nones were expected for the reaction of each carbonyl with
ammonium acetate in the first step of the reaction which
would result in the formation of regioisomers A or B
White solid; recystalized from ethanol, 70 % yield; mp
>255 °C. IR (KBr): 3310.0 (N–H), 1674.8 (cm−1) (N–
C=O). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.99–8.03
(m, 8H, Ar), 8.08–8.10 (m, 4H, Ar), 12.69 (s, 2H, NH).
13C NMR (100 MHz, DMSO-d6) δ (ppm): 135.8, 159.7,
161.9, 162.1, 164.9. MS (EI, 70 eV): m/z (%) = 456 (2.6),
455 (13.1), 454 (31.6), 453 (10.4), 352 (5.6), 351 (29.3),
350 (base peak), 349 (37.1), 201 (43.9), 107 (26.1). Anal.
Calcd for C28H18F4N2: C, 73.36; H, 3.96; F, 16.58; N, 6.11;
Found: C, 73.08; H, 4.02; N, 6.03.
1
(Scheme 2) [34]. The H-NMR and 13C-NMR of pyrroles
(1d and 1i) showed the chemical shifts δH and δC at 2.16
and 12.7 for 1d and 2.26 and 12.7 ppm for 1i, respectively.
So, they correlated with the A isomer.
A proposed mechanism for the formation of pyr-
role according to these electronic effects is outlined in
Scheme 3 [32–34]. It seems that ketone group of 1,3-dicar-
bonyl compound reacts initially with NH4OAc to form an
imine intermediate (I) that subsequently condenses with
activated benzoin (II) by acidic alumina to produce a cyclic
intermediate (III). Dehydration of this intermediate and
elimination of water produce the corresponding tetrasubsti-
tuted pyrrole (Scheme 3).
It is worth mentioning that when 1,3-diphenyl-propane-
1,3-dione was treated with benzoin and ammonium acetate
under optimized conditions, a by-product was the major
product instead of the corresponding pyrrole (Scheme 4).
After characterization, it was determined that the by-prod-
uct is 1,4-dihydro-tetra-phenylpyrazine.
Also, the same product (1,4-dihydro-tetraphenylpyra-
zine) was obtained when 3-oxo-hexanoic acid ethyl ester
was reacted with benzoin and ammonium acetate under
optimized conditions.
So, we conduct the reaction without 1,3-dicarbonyl
compounds as follows; benzoin (2 mmol) and ammo-
nium acetate (3 mmol) in ethanol (3 mL) and acidic alu-
mina (0.05 g) under reflux conditions, and the correspond-
ing 1,4-dihydro-tetraphenylpyrazine were obtained after
100 min in 85 % yield (Table 3). As shown in Table 3,
Results and discussion
The synthesis of highly substituted pyrroles from electron-
rich benzoins is failed by acid-catalyzed methods [32, 33].
There are a few reports in the literature which able to pro-
duce highly substituted pyrroles from electron-rich benzo-
ins [34, 38]. So, a model study was initiated with 1,2-di-
p-tolyl-ethane-1,2-dione, acetylacetone, ammonium salts,
and using various commercially acid or Lewis acid cata-
lysts (ZnCl2, CuCl2, FeCl2, silica, and Al2O3) in refluxing
ethanol (Scheme 1, Table 1).
As shown in Table 1, the best results were obtained
when acidic alumina was used as catalyst. In addition, basic
alumina gave the corresponding product in 60 % yield after
1 h in refluxing ethanol (Table 1, entry 7).
Moreover, the model reaction was treated in different
solvents such as ethanol, water, chloroform, tetrahydro-
furan, and acetonitrile in the presence of acidic alumina
(0.04 g, 0.04 mol %) as catalyst at refluxing conditions
(Table 1, entries 9–15). Although the result under solvent-
free conditions at 80 °C gave the corresponding product
after 60 min in 70 % yield (Table 1, entry 6), we choose the
ethanol as it is relatively benign organic solvent.
1 3

J IRAN CHEM SOC
Scheme 3 Proposed mecha-
nism for the synthesis of
2,3,4,5-tetrasubstituted pyrroles
catalyzed by acidic alumina
R
O
O
O
Ar
Al2O3
Ar
OH
R1
NH4OAc
HO
O
Ar
Ar
H
R
Al2O3
II
R1
I
NH
:
O
O
R
OH H
N
Ar
R1
Al2O3
HO
Ar
H
III
O
-H2O
R1
R
Al2O3
Ar
Ar
H
O
R
O
H
O
R
Ar
R1
H
H
N
Ar
Ar
R1
H
1
HO
N
H
Ar
N
H
HO
-H2O
O
Ph
Ph
H
Ph
Ph
O
Ph
Ph
Ph
Ph
N
Ph
Ph
O
O
Acidic Alumina
Refluxing Ethanol
+
+
NH4OAc
OH
Ph
Ph
N
H
N
H
Minor
(1.5 mmol)
Major
(1 mmol)
(1 mmol)
Scheme 4 Investigation the reaction of 1,3-diphenyl-propane-1,3-dione as 1,3-dicarbonyl compound
Table 3 Acidic alumina-catalyzed synthesis of 1,4-dihydro-tetrasubstituted pyrazines.
Acidic alumina
(0.05 g, 50 mol%)
H
Ar
Ar
O
Ar
Ar
N
Ar
Ar
NH4OAc
3 mmol
+
OH
N
H
Ethanol/ Reflux
2 mmol
2a-2c
Entry
Ar
Product
Time (min)
Yield (%)a
mp (°C)
Lit. mp (oC)
1
2
C6H5–
2a
2b
2c
100
100
100
85
83
84
>255
>255
>255
265 [48]
4-MeO–C6H4–
4-F–C6H4–
–
–
3
a
Isolated yield
1 3

J IRAN CHEM SOC
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Acknowledgments We are thankful to Persian Gulf University
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