Zinc tetrafluoroborate-catalysed synthesis of highly substituted pyrroles by a solvent-free reaction

Article abstract of DOI:10.1070/MC2006v016n04ABEH002287

A simple and highly efficient synthesis of penta- and tri-substituted pyrroles has been developed using the Paal-Knorr reaction catalysed by aqueous zinc tetrafluoroborate at room temperature under solvent-free conditions.

Full text of DOI:10.1070/MC2006v016n04ABEH002287

Mendeleev
Communications
Mendeleev Commun., 2006, 16(4), 220–221
Zinc tetrafluoroborate-catalysed synthesis of highly substituted pyrroles
by a solvent-free reaction
Brindaban C. Ranu,* Sudip Ghosh and Arijit Das
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata – 700 032, India.
Fax: +91 33 2473 2805; e-mail: ocbcr@iacs.res.in
DOI: 10.1070/MC2006v016n04ABEH002287
A simple and highly efficient synthesis of penta- and tri-substituted pyrroles has been developed using the Paal–Knorr reaction
catalysed by aqueous zinc tetrafluoroborate at room temperature under solvent-free conditions.
Pyrroles are important heterocyclic constituents of natural pro-
ducts,1 bioactive molecules2 and electrically conducting mate-
rials.3 Hence, substantial efforts have been made to develop
efficient methods for the synthesis of these compounds.4 The
Paal–Knorr reaction, in which 1,4-dicarbonyl compounds are con-
verted into pyrroles via acid-mediated cyclization with primary
amines, remains most common and attractive. Procedures using
catalysts such as potassium exchanged layered zirconium phos-
phate (1–24 h, room temperature),4(a) montmorillonite–KSF
(10–25 h, room temperature),4(b) ionic liquid (0.5–6 h, room
temperature),4(c) Bi(OTf)3/[bmIm]BF4 (4–5 h, 90 °C),4(d) micro-
wave (3 min)4(e),4(f),4(o) and Bi(NO3)3 (10–25 h, room tempera-
ture)4(g) have been employed for the Paal–Knorr synthesis of
pyrroles. There are also other approaches to the synthesis of these
compounds.4(h)–(n) However, these procedures provide primarily
tri-substituted pyrroles and access to tetra- and penta-substituted
ones is very limited.4(f),4(k) Many of these procedures require long
reaction times and expensive catalysts.
withdrawing and electron-donating substituents on the 1,4-di-
ketones are well acceptable in this procedure.
In general, the reactions are very clean, fast and high yielding.
This procedure gives an easy access to penta-substituted pyrroles,
†
General procedure for the synthesis of pyrroles. A mixture of a primary
amine (1.2 mmol) and 1,4-diketone (1 mmol) was stirred at room tem-
perature in the presence of a catalytic amount (0.01 ml, 2 mol%) of an
aqueous solution (40%) of zinc tetrafluoroborate for a few minutes as
required to complete the reaction (TLC). The reaction mixture was
then extracted with diethyl ether (3×10 ml), and the extract was washed
successively with aqueous HCl (1.3 N) and water. It was then dried
(Na2SO4) and evaporated to leave the crude product, which was purified
by column chromatography on silica gel (hexane–ethyl acetate, 95:5)
to provide the pure product (61–90%). The new compounds (Table 1,
entries 2, 3, 5–11) are properly characterised by their spectroscopic data
(IR, 1H and 13C NMR) and elemental analyses.
Entry 2: white solid, mp 48 °C. IR (n/cm–1): 1429, 1544, 1693. 1H NMR
(300 MHz, CDCl3) d: 0.88 (t, 3H, J 5.1 Hz), 1.13–1.19 (m, 2H), 1.24 (t,
6H, J 7.1 Hz), 1.42–1.50 (m, 2H), 2.19 (s, 6H), 3.67 (t, 2H, J 7.8 Hz),
4.15 (q, 4H, J 7.1 Hz). 13C NMR (75 MHz, CDCl3) d: 10.5 (2C), 13.4,
13.9 (2C), 22.0, 32.1, 43.2, 59.6 (2C), 115.6 (2C), 132.5 (2C), 165.5
(2C). Found (%): C, 65.35; H, 8.77; N, 4.56. Calc. for C16H25NO4 (%):
C, 65.06; H, 8.53; N, 4.74.
We report here a very simple and efficient methodology for
the synthesis of penta- and tri-substituted pyrroles by the Paal–
Knorr reaction catalysed by aqueous zinc tetrafluoroborate5
without any organic solvent (Scheme 1).
Entry 3: white solid, mp 53 °C. IR (n/cm–1): 1544, 1683, 1703. 1H NMR
(300 MHz, CDCl3) d: 0.89 (t, 3H, J 6.3 Hz), 1.21–1.31 (m, 6H), 1.38 (t,
6H, J 7.2 Hz), 1.54–1.61 (m, 2H), 2.36 (s, 6H), 3.73 (t, 2H, J 7.8 Hz),
4.25 (q, 4H, J 7.2 Hz). 13C NMR (75 MHz, CDCl3) d: 10.6 (2C), 13.7,
14.0 (2C), 22.3, 26.2, 30.1, 31.1, 43.6, 59.8 (2C), 112.0 (2C), 132.5
(2C), 165.6 (2C). Found (%): C, 66.57; H, 8.91; N, 4.15. Calc. for
C18H29NO4 (%): C, 66.84; H, 9.04; N, 4.33.
R1
R1
O
R1
Zn(BF4)2
Me
+
R2NH2
room
temperature
Me
Me
Me
N
R1
O
R2
Scheme 1
Entry 5: reddish gummy oil. IR (n/cm–1): 1382, 1610, 1701. 1H NMR
(300 MHz, CDCl3) d: 1.23 (t, 6H, J 7.0 Hz), 2.03 (s, 6H), 3.76 (s, 3H),
4.18 (q, 4H, J 7.0 Hz), 6.89 (d, 2H, J 7.0 Hz), 6.97 (d, 2H, J 7.0 Hz).
13C NMR (75 MHz, CDCl3) d: 11.5 (2C), 14.1 (2C), 55.3, 59.9 (2C),
112.1 (2C), 114.5 (2C), 128.9 (2C), 129.2, 134.3 (2C), 159.6, 165.5 (2C).
Found (%): C, 66.08; H, 6.66; N, 3.99. Calc. for C19H23NO5 (%): C,
66.07; H, 6.71; N, 4.06.
1,4-Diketones were condensed with aliphatic and aromatic
amines by this reaction to produce substituted pyrroles.† The
results are summarised in Table 1. Functional groups such as
OMe, CO2H, OH, Cl and SH on the amines remained intact
under the reaction conditions. On the other hand, both electron-
220 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(4), 220–221
In conclusion, the present procedure using an inexpensive
Table 1 Synthesis of pyrroles catalysed by Zn(BF4)2.
catalyst like zinc tetrafluoroborate provides a very simple one-pot
synthesis of pyrroles. The significant advantages offered by this
procedure are: (a) easy access to highly functionalised units;
(b) faster reaction (5–60 min) compared to other methods; (c) mild
conditions (room temperature); (d) organic solvent-free reaction
and (e) cost effectiveness.
Entry
R1
R2
t/min
Yield (%)a
Ref.
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
H
H
H
H
H
H
PhCH2
n-Butyl
n-Hexyl
Ph
20
5
89
95
90
90
92
90
70
61
92
93
88
95
85
95
90
96
87
92
93
96
93
92
25
30
20
60
15
25
30
30
30
5
7
p-MeOC6H4
p-HO2CC6H4
o-HSC6H4
o-MeC6H4
p-BrC6H4
NHPh
H2NCH2CH2
PhCH2
Cyclohexyl
n-Hexyl
This study was supported by CSIR, New Delhi [grant no.
01(1936)/04]. S.G. and A.D. acknowledge the support of CSIR
for their fellowships.
References
4(b)
4(c)
8
4(b)
9
4(e)
4(a)
10
1
2
R. A. Jones, Pyrroles, Part II, Wiley, New York, 1992.
15
5
(a) A. Furstner, H. Szillat, B. Gabor and R. Mynott, J. Am. Chem. Soc.,
1998, 120, 8305; (b) J. A. H. Lainton, J. W. Hoffman, B. R. Martin and
D. R. Compton, Tetrahedron Lett., 1995, 36, 1401; (c) C. Y. De Leon
and B. Ganem, Tetrahedron, 1997, 53, 7731.
Ph
10
10
30
10
5
8
15
10
p-HO2CC6H4
m-ClC6H4
o-HOC6H4
o-HSC6H4
o-MeOC6H4
α-Naphthyl
H2NCH2CH2
3
4
(a) A. Furstner, Synlett., 1999, 1523; (b) S. Higgins, Chem. Soc. Rev.,
1997, 26, 247.
(a) M. Curini, F. Montanari, O. Rosati, E. Lioy and R. Margarita,
Tetrahedron Lett., 2003, 44, 3923; (b) B. K. Banik, S. Samajdar and
I. Banik, J. Org. Chem., 2004, 69, 213; (c) B. Wang, Y. Gu, C. Luo,
T. Yang, L. Yang and J. Suo, Tetrahedron Lett., 2004, 45, 3417;
(d) J. S. Yadav, B. V. S. Reddy, B. Eeshwaraiah and M. K. Gupta,
Tetrahedron Lett., 2004, 45, 5873; (e) T. N. Danks, Tetrahedron Lett.,
1999, 40, 3957; (f) G. Minetto, L. F. Raveglia and M. Taddei, Org.
Lett., 2004, 6, 389; (g) B. K. Banik, I. Banik, M. Renteria and S. K.
Dasgupta, Tetrahedron Lett., 2005, 46, 2643; (h) B. Quiclet-Sire,
L. Quinkero, G. Sanchez-Jimenez and S. Z. Zard, Synlett., 2003, 75;
(i) J. Azizian, A. R. Karimi, Z. Kazemizadeh, A. A. Mohammadi and
M. R. Mohammadizadeh, J. Org. Chem., 2005, 70, 1471; (j) B. C. Ranu
and S. S. Dey, Tetrahedron, 2003, 44, 2865; (k) C. Agami, L. Dechoux,
L. Hamon and S. Hebbe, Synthesis, 2003, 859; (l) M. Periasamy,
G. Srinivas and P. Bharathi, J. Org. Chem., 1999, 64, 4204; (m)
B. Ramanathan, A. J. Keith, D. Armstrong and A. L. Odom, Org. Lett.,
2004, 6, 2957; (n) M. R. Tracey, R. Hsung and R. H. Lambeth, Synthesis,
2004, 918; (o) G. Minetto, L. F. Raveglia, A. Swga and M. Taddei, Eur.
J. Org. Chem., 2005, 5277.
11
4(b)
4(b)
H
H
aThe yields refer to those of the pure isolated products characterised by
spectroscopic (IR, 1H and 13C MNR) data.
which are not addressed adequately in the well-known proce-
dures.4 This also provides scope to put a substituent of choice in
the pyrrole ring by proper choice of the same in 1,4-diketone
and amine.
Entry 6: white solid; mp 185 °C. IR (n/cm–1): 1537, 1608, 1697, 2925,
2979. 1H NMR (300 MHz, CDCl3) d: 1.36 (t, 6H, J 7.0 Hz), 2.15 (s, 6H),
4.31 (q, 4H, J 7.0 Hz), 7.36 (d, 2H, J 8.4 Hz), 8.33 (d, 2H, J 8.4 Hz).
13C NMR (75 MHz, CDCl3) d: 11.6 (2C), 14.1 (2C), 60.2 (2C), 113.0
(2C), 128.2 (2C), 130.0, 131.4 (2C), 133.6 (2C), 141.2, 165.3 (2C),
170.2. Found (%): C, 63.32; H, 5.77; N, 3.73. Calc. for C19H21NO6 (%):
C, 63.50; H, 5.89; N, 3.90.
5
(a) B. C. Ranu, U. Jana and A. Majee, Tetrahedron Lett., 1999, 40,
1985; (b) B. C. Ranu, S. Samanta and S. K. Guchhait, Tetrahedron,
2002, 58, 983; (c) B. C. Ranu, J. Dutta and A. Das, Chem. Lett., 2003,
32, 366.
Entry 7: yellow gummy oil. IR (n/cm–1): 1541, 1701, 2981. H NMR
1
(300 MHz, CDCl3) d: 1.30 (t, 6H, J 7.2 Hz), 2.09 (s, 6H), 3.02 (s, 1H),
4.28 (q, 4H, J 7.2 Hz), 7.08–7.11 (m, 1H), 7.22–7.44 (m, 3H). 13C NMR
(75 MHz, CDCl3) d: 11.2 (2C), 14.2 (2C), 60.1 (2C), 113.2 (2C), 126.4,
129.3, 129.5, 129.9, 133.2, 133.6 (2C), 133.7, 165.4 (2C). Found (%):
C, 62.34; H, 5.92; N, 3.88. Calc. for C18H21NO4S (%): C, 62.23; H, 6.09;
N, 4.03.
6
7
8
9
M. A. Sukari and J. M. Vernon, Tetrahedron, 1983, 39, 793.
D. St. C. Black, Science of Synthesis, 2002, 9, 441.
Ph. Ng. Buu-Hoi, J. Chem. Soc., 1949, 2882.
Y. Chiang, R. L. Hinman, S. Theodoropulos and E. B. Whipple,
Tetrahedron, 1967, 23, 745.
Entry 8: yellow gummy oil. IR (n/cm–1): 1496, 1542, 1701. H NMR
1
10 Ph. Ng. Buu-Hoi, D. Ng. Xuong and J. M. Gazave, J. Org. Chem.,
(300 MHz, CDCl3) d: 1.30 (t, 6H, J 7.2 Hz), 1.93 (s, 3H), 2.04 (s, 6H),
4.29 (q, 4H, J 7.2 Hz), 7.06–7.09 (m, 1H), 7.29–7.37 (m, 3H). 13C NMR
(75 MHz, CDCl3) d: 11.2 (2C), 14.1 (2C), 17.0, 59.9 (2C), 112.4 (2C),
127.0, 128.2, 129.3, 131.0, 133.6, 135.6 (2C), 136.2, 165.4 (2C). Found
(%): C, 68.89; H, 6.86; N, 4.07. Calc. for C19H23NO4 (%): C, 69.28;
H, 7.04; N, 4.25.
1955, 20, 639.
11 J. A. Ragan, T. W. Makowski, M. J. Castaldi and P. D. Hill, Synthesis,
1998, 1599.
Entry 9: yellow solid; mp 86–88 °C. IR (n/cm–1): 1542, 1695, 1720.
1H NMR (300 MHz, CDCl3) d: 1.33 (t, 6H, J 7.0 Hz), 2.13 (s, 6H), 4.30
(q, 4H, J 7.0 Hz), 7.06 (d, 2H, J 8.4 Hz), 7.66 (d, 2H, J 8.4 Hz).
13C NMR (75 MHz, CDCl3) d: 11.6 (2C), 14.2 (2C), 60.1 (2C), 112.9
(2C), 123.1, 129.6 (2C), 132.8 (2C), 133.7 (2C), 135.7, 165.3 (2C).
Found (%): C, 54.55; H, 4.99; N, 3.23. Calc. for C18H20NO4Br (%):
C, 54.85; H, 5.11; N, 3.55.
Entry 10: yellow solid, mp 84–86 °C. IR (n/cm–1): 1602, 1701, 3269.
1H NMR (300 MHz, CDCl3) d: 1.90 (t, 6H, J 7.1 Hz), 2.73 (s, 6H), 4.84
(q, 4H, J 7.1 Hz), 7.03–7.05 (m, 2H), 7.40–7.45 (m, 1H), 7.72–7.77 (m,
2H), 8.04 (br. s, 1H). 13C NMR (75 MHz, CDCl3) d: 9.8 (2C), 14.1
(2C), 60.2 (2C), 110.0 (2C), 118.8 (2C), 120.6, 129.3 (2C), 134.8 (2C),
146.1, 165.5 (2C). Found (%): C, 65.23; H, 6.51; N, 8.27. Calc. for
C18H22N2O4 (%): C, 65.44; H, 6.71; N, 8.48.
Entry 11: white solid [a bis(pyrrole)], mp 196–198 °C. IR (n/cm–1):
1475, 1542, 1693. 1H NMR (300 MHz, CDCl3) d: 1.30 (t, 12H, J 7.0 Hz),
2.22 (s, 12H), 3.97 (s, 4H), 4.23 (q, 8H, J 7.0 Hz). 13C NMR (75 MHz,
CDCl3) d: 10.4 (4C), 14.2 (4C), 43.0 (2C), 60.1 (4C), 113.3 (4C), 132.4
(4C), 165.2 (4C). Found (%): C, 61.82; H, 7.15; N, 5.48. Calc. for
C26H36N2O8 (%): C, 61.89; H, 7.19; N, 5.55.
Received: 2nd December 2005; Com. 05/2629
Mendeleev Commun. 2006 221