Synthesis of cyanopyrroles

Article abstract of DOI:10.1055/s-1999-3669

Regioselective synthesis of α-cyanopyrroles (vs. α- alkoxycarbonylpyrroles) using oximinocyanoacetate esters in a Knorr-type reductive condensation with β-diketones can be directed by the presence of water. Thus, methyl oximinocyanoacetate was reacted with pentane-2,4-dione in hot acetic acid in the presence of zinc dust to give exclusively 3,5- dimethylpyrrole-2-carbonitrile when the acetic acid was wet; whereas, in glacial acetic acid only methyl 3,5-dimethylpyrrole-2-carboxylate was isolated (~40% yield).

Full text of DOI:10.1055/s-1999-3669

46
SHORT PAPER
Synthesis of Cyanopyrroles
Lingjiang Cheng, David A. Lightner*
Department of Chemistry, University of Nevada, Reno, Nevada 89557, USA
Fax: 702-784-6804
Received 7 May 1998; revised 25 June 1998
Subsequently, Clezy et al.5 repeated the Kleinspehn pro-
cedure to afford ethyl 2-cyano-3,5-dimethylpyrrole-4-
propanoate in moderate yield, with the corresponding eth-
yl pyrrole-2-carboxylate isolated as a minor byproduct.
Abstract: Regioselective synthesis of α-cyanopyrroles (vs.
α-alkoxycarbonylpyrroles) using oximinocyanoacetate esters in a
Knorr-type reductive condensation with â-diketones can be direct-
ed by the presence of water. Thus, methyl oximinocyanoacetate was
reacted with pentane-2,4-dione in hot acetic acid in the presence of Although other methods are now available to prepare
α-cyanopyrroles, e.g. by displacement of an α-bromo6 or
zinc dust to give exclusively 3,5-dimethylpyrrole-2-carbonitrile
when the acetic acid was wet; whereas, in glacial acetic acid only
methyl 3,5-dimethylpyrrole-2-carboxylate was isolated (~40%
α-acetoxynitroalkanes,7 the former requires strong elec-
yield).
by a BartonÐZard reaction using isocyanoacetonitrile and
tron-withdrawing groups at the â and α ' positions, and the
Key words: α-cyanopyrroles, oximinocyanoacetate, Knorr-type re-
action
latter affords an α′-free pyrrole. Since our interests lay in
preparing directly 2-cyanopyrroles with substituents at
pyrrole ring positions 3, 4 and 5, we reinvestigated Klein-
spehnÕs reaction.
For synthesis of cyanopyrroles, we used either methyl or
Over forty years ago, Kleinspehn described for the first
time how ethyl oximinocyanoacetate could be used in a
Knorr-type reductive condensation to synthesize α-cyano-
pyrroles. Thus, after mixing pentane-2,4-dione, ethyl ox-
iminocyanoacetate and anhydrous sodium acetate in
~12% aqueous acetic acid, addition of zinc dust at 95Ð
105¡C afforded a 35% crude yield of 3,5-dimethylpyrrole-
2-carbonitrile. A similar reaction using 3-ethylpentane-2,4-
dione gave 4-ethyl-3,5-dimethylpyrrole-2-carbonitrile in
45% crude yield. These two α-cyanopyrroles had been de-
scribed some 20Ð30 years earlier, prepared by Fischer et
al.2,3 by cyanation of the corresponding α-free pyrroles. The
Kleinspehn modification offered a simple and direct way to
prepare α-cyanopyrroles that was different from the then
known procedures.4 Interestingly, Kleinspehn noted that
the order of addition of reactants affected the course of the
reaction: when ethyl oximinocyanoacetate was added to a
mixture of zinc dust in a hot acetic acid containing pentane-
2,4-dione, a mixture of ethyl 3,5-dimethylpyrrole-2-car-
boxylate and 3,5-dimethylpyrrole-2-carbonitrile was ob-
tained, but when the zinc dust was added slowly with
stirring to a hot solution of the two organic reactants, only
the cyanopyrrole was obtained.
ethyl cyanoacetate (4 and 5, respectively) and either pen-
tane-2,4-dione (3a) or 3-[2-(methoxycarbonyl)ethyl]pen-
tane-2,4-dione (3b) as synthons in Scheme 1. As is
customary for Knorr-type pyrrole syntheses, zinc dust was
the reducing agent and acetic acid was the solvent. We
found that regioselectivity in the product formation de-
pended on the presence of water in the acetic acid solvent.
For reactions carried out in glacial acetic acid, the cyano-
pyrrole was not observed in the crude solid obtained after
quenching the reaction with water. However, when water
was present in the reaction solvent, as in 1:1 acetic acid/
water, the α-cyanopyrrole was found in the crude solid
obtained after quenching the reaction with water, but the
α-(m)ethoxycarbonylpyrrole was not observed (Table).
By varying the reaction temperature and time, we noted
that with longer reaction times, the product yields were al-
tered. Thus in 1:1 acetic acid/water, the yield of cyanopy-
rrole decreased when the reaction time was extended from
0.5 to 4 h but no α-(m)ethoxycarbonylpyrrole was found.
When the temperature was lowered from 80¡C to 50¡C, no
pyrrole products were isolated. For purposes of making
α-cyanopyrroles, there appears to be no advantage in using
5 or 4. As the ratio of acetic acid to water increases, e.g. to
2:1, a mixture of α-cyano and α-(m)ethoxycarbonylpyr-
roles is obtained. In glacial acetic acid, only the latter is
formed. Of course, a better synthesis of the latter is to use
(m)ethyl oximinoacetoacetate or di(m)ethyl oximinoma-
lonate as synthons in place of 4 or 5.8,9
Just how water acts to control the product distribution is
not entirely clear. We speculate that it becomes most im-
portant after the dihydroisopyrrole intermediate 6 is
formed (Scheme 2). The presence of water in the reaction
might lead to hydrolysis of the alkoxycarbonyl group
(CO2R') to the acid, which after decarboxylation and de-
hydration converts 6 to 1. When water is absent, a differ-
Scheme 1
Synthesis 1999, No. 1, 46Ð48 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Cyanopyrroles
47
Table Influence of Reaction Temperature and the Presence of Water on the Regioselectivity of the Pyrrole-Forming Condensation of Methyl
(4) or Ethyl Oximinocyanoacetate (5) with Pentane-2,5-dione (3a) and 3-(Methoxycarbonylethyl)pentane-2,4-dione (3b)a
Reactants
Dione
Reaction Conditions
Solvent
Yield (%) Producta
Oxime
Temp (°C)
Time (h)
1a
2a
1b
2b
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3a
3a
3a
3b
3b
3b
3b
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
AcOH/H2O (1:1)
AcOH/H2O (1:1)
AcOH/H2O (1:1)
AcOH
AcOH
AcOH
AcOH/H2O (1:1)
AcOH/H2O (1:1)
AcOH/H2O (1:1)
AcOH
80
80
50
80
80
50
80
80
50
80
50
80
80
80
80
80
50
50
0.5
4
4
0.5
4
4
0.5
4
4
4
4
0.5
0.5
4
0.5
0.5
4
38
25
13
0
0
0
–
–
–
–
0
0
0
–
–
–
–
–
–
23
0
21
0
–
–
–
–
–
–
0
28
<1
–
0
0
0
–
–
–
–
32
23
–
–
–
AcOH
–
26
4
0
AcOH/H2O (1:1)
AcOH/H2O (2:1)
AcOH
AcOH/H2O (1:1)
AcOH
0
–
–
–
27
0
10
37
–
0
–
–
–
–
0
–
–
–
16
12
40
AcOH
AcOH
0
0
11
a See Scheme 1 for structures; 2a = 2ac and 2b = 2bc when 4 is used; when 5 is used 2a = 2ad and 2b = 2bd.
was begun immediately. The addition was complete in 1Ð1.5 h. Stir-
ring was continued while the reaction temperature dropped to r.t.
After stirring at r.t. for 3 h, a precipitate began to form. Then the
mixture was diluted with water (100 mL) and allowed to stand at
10¡C for 3 h. The solid was collected by suction filtration and dried
in air to give a white product (64.47 g, 97%); mp 120Ð122¡C (lit.10
mp 124¡C).
IR (KBr): n = 3547, 3448 (OÐH), 2990 (CÐH), 2233 (CN), 1728
(C=O), 1654, 1434, 1314, 1067, 853, 768 cmÐ1.
1H NMR (300 MHz, D2O): d = 3.886 (s, 3H, CH3), 4.8 (br, HDO).
13C NMR (75 MHz, D2O): d = 53.662 (CH3), 111.611 (CN),
127.267 (C=N), 162.706 (C=O).
Scheme 2
GC-MS (tR 5.4 min): m/z = 128 (M+¥), 111 (M Ð OH), 97 (M Ð
OCH3), 69 (M Ð CO2CH3).
ent course is followed, where presumably acetate ion
attacks the CN group in preference to the (m)ethoxycarbo-
nyl group followed by elimination.
Ethyl Oximinocyanoacetate [Ethyl 2-Cyano-2-(hydroxyimi-
no)acetate] (5)
Ethyl cyanoacetate (119.7 g 1.06 mmol) was treated with NaNO2
(150 g, 2.17 mmol) as described earlier11 to give 5 as white needles
(130 g, 92%); mp 128Ð130¡C (lit.11 mp 131Ð133¡C).
IR spectra were recorded on PerkinÐElmer 1600 FTIR spectropho-
tometer. 1H NMR and 13C NMR spectra were recorded on a Varian
Unity 500 MHz spectrometer or a General Electric QE-300 spec-
trometer using CDCl3 as solvent and TMS as an internal standard.
GC-MS analyses were carried out on a HewlettÐPackard GC-MS
Model 5890A ion selective detector equipped with a DB-1 (100%
dimethylpolysiloxane) column. Mps are uncorrected. Combustion
analyses were carried out by the Desert Analytics Laboratory in
Tucson, Arizona. All reagents and solvents were from Fisher
Chemicals or ACROS Organics and were used without further pu-
rification.
IR (KBr): n = 3600, 3248 (OÐH), 3008, 2851 (CÐH), 2239 (CN),
1732 (C=O), 1636, 1594, 1452, 1319, 1062, 820, 763, 513 cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.407 (t, 3H, J = 6.84 Hz,
CH2CH3), 4.436 (q, 2H, J = 6.84 Hz, CH2CH3), 4.833 (br, 1H, OH).
13C NMR (75 MHz, CDCl3): d = 13.909 (CH2CH3), 63.58
(CH2CH3), 109.25, 109.46(CN), 126.46, 128.71 (C=N), 161.83
(C=O).
GC-MS (tR 7.2 min): m/z = 142 (M+¥), 125 (M Ð OH), 114 (M Ð
CH2CH2), 97 (M Ð OCH2CH3), 69 (M Ð CO2CH2CH3).
Methyl Oximinocyanoacetate [Methyl 2-Cyano-2-(hydroxyimi-
no)acetate] (4)
Synthesis of α-Cyanopyrroles or α-(M)ethoxycarbonylpyr-
roles; General Procedure
Equal molar amounts of oxime (4 or 5) and b-diketone (3a or 3b)
(10 mmol each) were dissolved in glacial AcOH (20 mL) or aq
AcOH (20 mL). The solution was warmed to a designated temper-
ature on an oil bath or a water bath. Into the rapidly stirred solution,
zinc dust (2.5 g-atoms) was added in small portions so that the tem-
Into a 500-mL three-neck round bottom flask equipped with a me-
chanical stirrer and a long stem funnel were placed glacial AcOH
(100 mL) and NaOH pellets (12 g). Stirring was begun, and over
10 min the pellets dissolved, bringing the mixture just barely to re-
flux. Methyl cyanoacetate (50.0 g, 0.50 mol) was added to the hot
solution and rinsed with glacial AcOH (5 mL). Slow dropwise ad-
dition of a solution of NaNO2 (80 g, 1.16 mol) in water (100 mL)
Synthesis 1999, No. 1, 46Ð48 ISSN 0039-7881 © Thieme Stuttgart · New York

48
L. Cheng, D. A. Lightner
SHORT PAPER
perature of the mixture was kept at 3Ð5¡C above the bath tempera-
ture. After all the zinc dust was added, the mixture was stirred on
the same bath for a time listed in the Table. (For reactions in aq
AcOH, excess zinc dust became small pearls at the end of the reac-
tion.) The mixture was poured into water (100 mL), and the precip-
itated pyrrole was collected by suction filtration and washed with
water. The product was crystallized once from 70% aq MeOH for
spectroscopic analyses.
Anal. Calcd for C11H14N2O4 (206.2): C, 64.06; H, 6.84; N, 13.58.
Found: C, 63.79; H, 6.70; N, 13.59
Methyl 2-Methoxycarbonyl-3,5-dimethylpyrrole-4-propanoate
(2bc)
Following the general procedure, in glacial AcOH solvent, 3b (1.9
g, 0.01 mol) was reacted with 4 at 50¡C for 4 h to give 0.55 g (23%)
of 2bc; mp 106Ð107¡C (lit.6 mp 108¡C).
IR (KBr): n = 3311 (NÐH), 2948 (CÐH), 1736, 1664 (C=O), 11500,
3,5-Dimethylpyrrole-2-carbonitrile (1a)
1451, 1418, 1372, 1298, 1269, 1218, 1178, 1091, 991, 774, 582 cmÐ1.
Following the general procedure, in AcOH/H2O (1:1) at 80¡C and
a 30 min reaction time, 3a (1.0 g, 0.01 mol) gave 0.46 g (38%) of
1a by reaction with 4 (1.3 g, 0.01 mol), and a 26% yield by reaction
with 5 (1.4 g, 0.01 mol); mp 75Ð76¡C (lit.1 mp 75Ð76.5¡C).
1H NMR (500 MHz, CDCl3): d = 2.215 (s, 3H, CH3), 2.267 (s, 3H,
CH3), 2.427 (t, 2H, J = 7.5 Hz, propanoic CH2), 2.704 (t, 2H, J =
7.5 Hz, propanoic CH2), 3.661 (s, 3H, CH3), 3.819 (s, 3H, CH3),
8.666 (br, 1H, N-H).
13C NMR (75 MHz, CDCl3): d = 10.47, 11.42, 19.59, 34.88, 50.88,
51.54, 116.79, 120.02, 127.07, 129.90. 161.99, 173.50.
IR (KBr): n = 3268 (NÐH), 2919 (CÐH), 2212 (CN), 1499, 1384,
1264, 800 cmÐ1.
1H NMR (300 MHz, CDCl3): d = 2.199 (s, 3H, CH3), 2.248 (s, 3H,
CH3), 5.791 (s, 1H, 4-H), 9.450 (br, 1H, N-H).
13C NMR (75 MHz, CDCl3): d = 11.59, 13.09, 97.10, 109.25,
115.55, 132.87, 134.29.
GC-MS (tR 12.0 min): m/z = 120 (M+¥), 119 (M Ð H), 105 (M Ð
CH3), 92, 65.
GC-MS (tR 15.2 min): m/z = 239 (M+¥), 208 (M+ Ð OCH3), 180 (M+
Ð CO2CH3), 166 (M+ Ð CH2CO2CH3), 134.
Methyl 2-Ethoxycarbonyl-3,5-dimethylpyrrole-4-propanoate
(2bd)
Following the general procedure, in glacial AcOH solvent, 3b (1.9
g, 0.1 mol) was reacted with 5 (1.4 g, 0.01 mol) at 50¡C for 11 h to
give 1.0 g (40%) of 2bd; mp 103Ð104¡C (lit.6 mp 104¡C).
Methyl 3,5-Dimethylpyrrole-2-carboxylate (2ac)
Following the general procedure, in glacial AcOH at 80¡C and a 4
h reaction time, 3a (1.0 g, 0.01 mol) and 4 (1.3 g, 0.01 mol) gave
0.43 g (28%) of 2ac; mp 94Ð96¡C (lit.12 no mp reported).
IR (KBr): n = 3304 (NÐH), 2949 (CÐH), 1735, 1661 (C=O), 1508,
1438, 1267, 1171, 1093, 1025, 777 cmÐ1.
1H NMR (300 MHz, CDCl3): d = 1.337 (t, 3H, J = 7.32 Hz,
CH2CH3), 2.209 (s, 3H, CH3), 2.263 (s, 3H, CH3), 2.419 (t, 2H, J =
8.30 Hz, propanoic CH2), 2.699 (t, 2H, J = 8.30 Hz, propanoic CH2),
3.661 (s, 3H, CH3), 4.280 (q, 2H, J = 7.32 Hz, CH2CH3), 8.638 (br,
1H, N-H).
GC-MS (tR 16.4 min): m/z = 253 (M+¥), 208 (M Ð OCH2CH3), 180
(M Ð CO2CH2CH3 or M Ð CH2CO2CH3), 134.
IR (KBr): n = 3292 (NÐH), 2956 (CÐH), 1684 (C=O), 1474, 1458,
1283, 1224, 1109, 802 cmÐ1.
1H NMR (300 MHz, CDCl3): d = 2.245 (s, 3H, CH3), 2.300 (s, 3H,
CH3), 3.824 (s, 3H, CH3), 5.796 (s, 1H, J = 2.3 Hz, 4-H), 8.758 (br,
1H, N-H).
GC-MS (tR 8.2 min): m/z = 153 (M+¥), 138 (M Ð CH3), 122 (M Ð
OCH3), 94 (M Ð CO2CH3), 66.
Acknowledgement
Ethyl 3,5-Dimethylpyrrole-2-carboxylate (2ad)
Following the general procedure, in glacial AcOH, at 50¡C and a 4
h reaction time, 3a (1.0 g, 0.01 mol) and 5 (1.4 g, 0.01 mol) gave
0.62 g (37%) of 2ad; mp 125Ð126¡C (lit.3 mp 125¡C).
We thank the U.S. National Institutes of Health (HD 17779) for
generous support of this work. L.C. is on leave from the Institute of
Photographic Chemistry, Beijing.
IR (KBr): n = 3296 (NÐH), 2981, 2929 (CÐH), 1658 (C=O),
1454,1272, 1218, 1121, 1105, 1026, 801 cmÐ1.
References
1H NMR (300 MHz, CDCl3): d = 1.350 (t, 3H, J = 6.84 Hz, CH2CH3),
2.248 (s, 3H, CH3), 2.305 (s, 3H, CH3), 4.294 (q, 2H, J = 6.84 Hz,
CH2CH3), 5.793 (s, 1H, J = 2.3 Hz, 4-H), 8.760 (br, 1H, N-H).
GC-MS (tR 9.4 min): m/z = 167 (M+¥), 138 (M Ð CH2CH3), 122 (M
Ð OCH2CH3), 94 (M Ð CO2CH2CH3), 66.
(1) Kleinspehn, G. G. J. Am. Chem. Soc. 1955, 77, 1546.
(2) Fischer, H.; Halbig, P.; Walach, B. Liebigs Ann. Chem. 1927,
452, 296.
(3) Fischer, H.; Csukas, A. Liebigs Ann. Chem. 1933, 508, 183.
(4) Fischer H.; Orth, H. Die Chemie des Pyrrols; Akademische
Verlagsgesellschaft, GmbH: Leipzig, 1934; Vol. I.
(5) Chong, R.; Clezy, P. S.; Liepa, A. J.; Nichol, A. W. Aust. J.
Chem. 1969, 22, 229.
Methyl 2-Cyano-3,5-dimethylpyrrole-4-propanoate (1b)
Following the general procedure, in AcOH/H2O (1:1) solvent b-
diketone 3b (1.9 g, 0.01 mol) was reacted with 4 (1.3 g, 0.01 mol)
at 80¡C for 30 min to give 0.47 g (23%) of 1b; mp 73Ð74¡C; reac-
tion of 3b with 5 gave a 27% yield of 1b.
(6) Cirrincione, G.; Almerico, A. M.; Passannanti, A.; Diana, P.;
Mingoia, F. Synthesis 1997, 1169.
(7) Adamczyk, M.; Reddy, R. E. Tetrahedron Lett. 1995, 36,
7983.
(8) Shrout, D. P.; Lightner, D. A. Synthesis 1990, 1062.
(9) Xie, M.; Lightner, D. A. Tetrahedron 1993, 49, 2185.
(10) Rose, J-C.; Pradere, J. P.; Duguay, G.; Guevel, A.; Quiniou,
H.; Poignant, S. Can. J. Chem. 1983, 61, 1169.
(11) Fields, M.; Walz, D. E.; Rothchild, S. J. Am. Chem. Soc. 1951,
73, 1000.
IR (KBr): n = 3310 (NÐH), 2959 (CÐH), 2199 (CN), 1708 (C=O),
1432, 1370, 1303,1256, 1209 cmÐ1.
1H NMR (500 MHz, CDCl3): d = 2.151 (s, 3H, CH3), 2.208 (s, 3H,
CH3), 2.440 (t, 2H, J = 7.5 Hz, propanoic CH2), 2.691 (t, 2H, J =
7.5 Hz, propanoic CH2), 3.669 (s, 3H, CH3), 8.645 (br, 1H, NÐH).
13C NMR (500 MHz, CDCl3): d = 10.02, 11.48, 19.53, 34.55, 51.64,
97.07, 115.10, 118.73,131.11, 131.19, 173.42.
(12) Stern, A.; Klebs, G. Liebigs Ann. Chem. 1933, 500, 91.
GC-MS (15.8 min): m/z = 206 (M+¥), 174 (M Ð HOCH3), 133 (M Ð
CH2CO2CH3).
Synthesis 1999, No. 1, 46Ð48 ISSN 0039-7881 © Thieme Stuttgart · New York