Synthesis of highly substituted pyrroles via nucleophilic catalysis

Article abstract of DOI:10.1021/jo1011448

Figure presented. A nucleophilic catalysis method providing a concise synthesis of di-, tri-, and tetrasubstituted pyrroles is described. This regioselective one-pot method relies on nucleophilic catalysis of the intermolecular addition of oximes to activ

Full text of DOI:10.1021/jo1011448

pubs.acs.org/joc
SCHEME 1. Trofimov Pyrrole Synthesis and Proposed
Mechanism
Synthesis of Highly Substituted Pyrroles
via Nucleophilic Catalysis
Simbarashe Ngwerume and Jason E. Camp*
School of Chemistry, University of Nottingham,
Nottingham NG7 2RD, U.K.
jason.camp@nottingham.ac.uk
Received June 11, 2010
Paal-Knorr pyrrole synthesis.7 Importantly, this reaction
provides (a) access to difficult to synthesize pyrroles from
unactivated alkynes, and (b) a convergent way to form both a
C-C bond and a C-N bond.8 Unfortunately, the usual
reaction conditions are extremely harsh, requiring strong
bases/high temperatures. Additionally, the process is un-
selective, resulting in a mixture of both product regioisomers
and distribution (i.e., formation of 5-7 from the reaction of
oxime 1a and phenylacetylene). These factors limit the over-
all synthetic utility of the Trofimov pyrrole synthesis, and
therefore, we sought to develop a milder catalytic version to
broaden the scope of this important transformation.
At the outset of our research, nothing had been reported
on catalytic variants of the Trofimov reaction. During the
course of the work outlined here, Anderson et al. described a
related study on the selective formation of methyl-substi-
tuted pyrroles from O-allyl oximes. Vinyl oxime intermedi-
ates similar to 2 are formed in situ using an iridium-catalyzed
isomerization of preformed allyl oximes, which then under-
went a process similar to that outlined in Scheme 1 to form
4-methyl-5-unsubstituted pyrroles (Figure 1).9 This publica-
tion has prompted us to disclose our research in the area of
catalytic variants of the Trofimov reaction, which eliminates
the need for strongly basic conditions while controlling the
regioselectivity of the reaction and increasing the scope/
utility of the products. Herein we report the findings from
our study, including the development of a one-pot nucleo-
philic catalysis method for the synthesis of highly substituted
pyrroles from the reaction of oximes with electron-deficient
alkynes.
A nucleophilic catalysis method providing a concise syn-
thesis of di-, tri-, and tetrasubstituted pyrroles is de-
scribed. This regioselective one-pot method relies on
nucleophilic catalysis of the intermolecular addition of
oximes to activated alkynes and thermal rearrangement of
the in situ generated O-vinyl oximes to form pyrroles that
contain a functional group handle at the C3/C4 position.
Pyrroles as pharmaceuticals,1 agrochemicals,2 and in bio-
logical processes3 are vital to our everyday lives. Due to their
importance, extensive research has been conducted on the
synthesis of pyrroles.4 One underutilized method for the
synthesis of pyrroles is the reaction of oximes and acetylenes
under thermal superbasic conditions (LiOH, DMSO), the
Trofimov reaction (Scheme 1).5,6 Mechanistically, this pro-
cess is proposed to proceed via initial addition of the anion of
oxime 1a to the alkyne, followed by tautomerization of vinyl
oxime 2 to diene 3. A subsequent [3,3]-sigmatropic rearran-
gement forms 1,4-iminoaldehyde 4, which upon cyclodehy-
dration generates pyrrole 5, in a manner analogous to the
To begin, the formation of vinyl oximes from the addition
of oximes to activated alkynes was investigated. Impor-
tantly, we wanted to develop a synthesis of vinyl oximes that
(1) For example, see: (a) Pinna, G. A.; Curzu, M. M.; Sechi, M.; Chelucci,
G.; Maciocco, E. Il Farmaco 1999, 54, 542–550. (b) Murineddu, G.; Loriga,
ꢀ
G.; Gavini, E.; Peanna, A. T.; Mule, A. C.; Pinna, G. A. Arch. Pharm. Med.
Chem. 2001, 334, 393–398.
(2) Walter, H. Z. Naturforsch. 2008, 63b, 351–362.
(3) For example, see: Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–
7256.
(4) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Blackwell
Science: Oxford, UK, 2010.
(5) For a review, see: Mikhaleva, A. I.; Hyun, S.; Trofimov, B. A.
Heterocycles 1994, 37, 1193–1232. (b) Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 2001, 2491–2515.
(6) For examples of Trofimov reactions, see: (a) Petrova, O. V.; Sobenina,
L. N.; Ushakov, I. A.; Mikhaleva, A. I.; Hyun, S.; Trofimov, B. A. ARKIVOC
2009, iv, 14–20. (b) Trofimov, B. A.; Schmidt, E. A.; Mikhaleva, A. I.; Pozo-
Gonzaol, C.; Pomposo, J. A.; Salsamendi, M.; Protzuk, N. I.; Zorina, N. V.;
Afonin, A. V.; Vashchenko, A. V.; Levanova, E. P.; Levkovskaya, G. G.
Chem.;Eur. J. 2009, 15, 6435-6445 and references therein.
(7) For a recent microwave-assisted Paal-Knorr pyrrole synthesis, see:
Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389–392.
(8) For examples of the use of the Trofimov reaction in synthesis, see:
(a) Gonzales, F.; Sanz-Cervera, J. F.; William, R. M. Tetrahedron Lett. 1999,
40, 4519–4522. (b) Pinna, G. A.; Pirisi, M. A.; Chelucci, G.; Mussinu, J. M.;
Murineddu, G.; Lorga, G.; D’Aquila, P. S.; Serra, G. Bioorg. Med. Chem.
2002, 10, 2485–2496. (c) Murineddu, G.; Cignarella, G.; Chelucci, G.; Loriga,
G.; Pinna, G. A. Chem. Pharm. Bull. 2002, 50, 754–759. (d) Vasil’tsov, A. M.;
Ivanov, A. V.; Mikhaleva, A. I.; Trofimov, B. A. Tetrahedron Lett. 2010, 51,
1690–1692.
(9) Wang, H.; Mueller, D. S.; Sachwani, R. M.; Londino, H. N.; Anderson,
L. L. Org. Lett. 2010, 12, 2290–2293.
DOI: 10.1021/jo1011448
r
Published on Web 08/18/2010
J. Org. Chem. 2010, 75, 6271–6274 6271
2010 American Chemical Society

Ngwerume and Camp
JOCNote
TABLE 2. Thermal Rearrangement of Vinyl Oximes to Pyrroles
entry
solvent/conditions
result/yield (%)
1
2
3
4
5
6
7
8
none, thermal, 100 °C, 26 h
9b
9b
9b
9b
9b
9b
9b
10b/84
none, thermal, 120 °C, 28 h
none, thermal, 140 °C, 24 h
DMSO, microwave, 120 °C, 45 min
toluene, microwave, 100 °C, 45 min
toluene, microwave, 120 °C, 45 min
toluene, microwave, 140 °C, 45 min
toluene, microwave, 170 °C, 45 min
FIGURE 1. Catalytic synthesis of pyrroles from oximes.
TABLE 1. O-Vinyl Oxime Formation via Nucleophilic Catalysis
SCHEME 2. Substituted Oxime Formation
entry
catalyst/conditions
yield (%) E:Z ratio
1
2
3
4
5
6
7
8
PPh3, DCM, -10 °C-rt, 20 h
65, 9:1
71, 9:1
72, 8:1
66, 8:1
55,a 8:1
70,a 8:1
80,a 9:1
71,a 10:1
DMAP, DCM, -10 °C-rt, 20 h
DABCO, DCM, -10 °C-rt, 20 h
DABCO, toluene, -10 °C-rt, 20 h
PPh3, toluene-d8,40 °C, microwave, 10 min
PPh3, toluene-d8,60 °C, microwave, 10 min
PPh3, toluene-d8,80 °C, microwave, 10 min
PPh3, toluene-d8,100 °C, microwave, 10 min
aPercent conversion to product based on NMR analysis.
would be viable under the subsequent thermal rearrange-
ment (vide infra). Yavari and Ramazani reported a method
for the synthesis of vinyl oximes based on the use of
triphenylphosphine (PPh3) as a nucleophilic catalyst.10,11
Building upon this research, a number of nucleophilic cata-
lysts (PPh3, DMAP, and DABCO) were shown to effect the
formation of vinyl oxime 9b. Reaction of acetophenone
oxime (1b) with ethyl propiolate (8) in either DCM or toluene
at rt cleanly afforded the desired product 9b, as an insepar-
able mixture of E:Z-alkene isomers (Table 1, entries 1-4).12
Next, the thermal stability of this reaction was investigated
by analyzing the contents of the crude reaction mixture after
microwave irradiation.13 The optimal temperature for the
formation of vinyl oxime 9b was found to be 80 °C (Table 1,
entries 5-8).
electron-withdrawing groups requiring increased tempera-
tures.15 Neat thermolysis for extended reaction times at
temperatures up to 140 °C using traditional heating did not
afford any of the desired pyrrole 10b (Table 2). In contrast,
DMSO at 120 °C, a solvent and temperature that have been
shown to result in the formation of pyrroles from unsubsti-
tuted vinyl oximes,16 only afforded starting material 9b.
To overcome the activation barrier for conversion of vinyl
oximes with electron-withdrawing groups to pyrroles, 9b was
heated in toluene to 170 °C in a microwave reactor, which
gave the desired pyrrole 10b in 84% isolated yield.
The second phase of this work was directed toward the
thermal rearrangement of vinyl oxime 9b to 2,4-disubstituted
pyrrole 10b. Previous research on the thermal rearrange-
ment14 of vinyl oximes to pyrroles demonstrated that the
reaction is dependent upon the nature of the substrate with
We next investigated a one-pot synthesis of pyrroles
from oximes and activated alkynes. A series of oximes were
initially synthesized under standard conditions (Scheme 2).17,18
Oximes 1a-1f were isolated as the (E)-oximes, as determined
by correlation to literature precedent, while oximes 1h-1k
were isolated as isomers.
(10) (a) Yavari, I.; Ramazani, A. Synth. Commun. 1997, 27, 1449–1454.
(b) For a review of PPh3 as a nucleophilic catalyst, see: Lu, X.; Zhang, C.; Xu,
Z. Acc. Chem. Res. 2001, 34, 535–544.
(11) For a related nucleophilic catalysis approach to N-hydroxy pyrroles,
see: Hekmatshoar, R.; Nouri, R.; Beheshtiha, S. Y. S. Heteroat. Chem. 2008,
19, 100-103 and references therein.
Oximes 1a-1k were then reacted with activated alkynes,
ethyl propiolate (8) or dimethylacetylenedicarboxylate (12),
to form highly substituted pyrroles 10 or 13, respectively
(12) For use of nucleophilic catalysts in the related Morita-Baylis-Hill-
man reaction, see: (a) Spivey, A. C.; Areniyadis, S. Angew. Chem., Int. Ed.
2004, 43, 5436–5441. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001–8062.
(15) For examples, see: (a) Sheradsky, T. Tetrahedron Lett. 1970, 25–26.
(b) Pinna, G. A; Sechi, M.; Paglietti, G.; Pirisi, M. A. J. Chem. Res. (S) 2003,
117-120 and references therein.
(16) Schmidt, E. Y.; Zorina, N. V.; Zaitsez, A. B.; Mikhaleva, A. I.;
ꢁ
Vasil’tsov, A. M.; Audebert, P.; Clavier, G.; Meallet-Renault, R.; Pansu,
R. B. Tetrahedron Lett. 2004, 45, 5489–5491.
(17) Cui, Y.; Yasutomi, E.; Otani, Y.; Yoshinaga, T.; Ido, K; Sawada, K.;
Kawahata, M.; Yamaguchi, K; Ohwada, T. Bioorg. Med. Chem. Lett. 2008,
18, 6386–6389.
(18) See Supporting Information for details on the synthesis and char-
acterization of oximes 1a-1k.
(13) For a review on microwave-assisted multicomponent reactions for
the synthesis of heterocycles, see: Bagley, M. C.; Lubinu, M. C. Top.
Heterocycl. Chem. 2006, 31–58.
(14) Please note that unsubstituted vinyl oximes have been shown to
explode violently at elevated temperatures. See: Trofimov, B. A.; Mikhaleva,
A. I.; Vasol’tsov, A. M.; Schmidt, E. Y.; Tarasova, O. A.; Morozova, L. V.;
Sobenina, L. N.; Preiss, T.; Henkelmann, J. Synthesis 2000, 1125–1132.
6272 J. Org. Chem. Vol. 75, No. 18, 2010

Ngwerume and Camp
JOCNote
SCHEME 3. One-pot Pyrrole Synthesis from Oximes and
Activated Alkynes
C4 for further manipulations and negates the need for
strongly basic conditions. To the best of our knowledge, this
is the first example of a catalytic one-pot method for the
direct synthesis of pyrroles from oximes and activated
alkynes, and we anticipate that it will find wide application
due to its simple operating procedure.
Experimental Section
Ethyl 3-(1-phenylethylideneaminooxy)acrylate (9b). To a stir-
red solution of DABCO (36 mg, 0.30 mmol) and (E)-acetophe-
none oxime (1b, 400 mg, 3.0 mmol) in dry dichloromethane
(8 mL) at -10 °C was added dropwise a mixture of ethyl
propiolate (8, 0.28 mL, 3.0 mmol) in dichloromethane (3 mL)
over 15 min. The reaction mixture was allowed to warm to room
temperature and stirred for 20 h. The mixture was concentrated
under reduced pressure and the residue purified by flash column
chromatography on silica gel (9:1 petroleum/EtOAc) to afford
ethyl 3-(1-phenylethylideneaminooxy)acrylate (9b, 497 mg,
72%) as an inseparable E:Z mixture (8:1) as a colorless oil: IR
(CHCl3) ν (cm-1) 3180, 2961, 2872, 2728, 1701, 1615, 1573,
1465, 1312, 1129, 1048, 896, 840, 640 cm-1. (E)-Isomer: 1H
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 12.6 Hz, 1H), 7.67-7.74
(m, 2H), 7.37-7.46 (m, 3H), 5.71 (d, J = 12.6 Hz, 1H), 4.22 (q,
J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR
(400 MHz, CDCl3) δ 167.6, 161.9, 160.3, 134.5, 130.4, 128.6,
1
126.9, 126.9, 97.3, 59.8, 14.3, 13.5. (Z)-Isomer: H NMR (400
MHz, CDCl3) δ 7.68-7.77 (m, 2H), 7.49 (d, J = 7.5 Hz, 1H),
7.45-7.49 (m, 3H), 4.94 (d, J = 7.5 Hz, 1H), 4.24 (q, J = 7.1 Hz,
2H), 2.48 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (400 MHz,
CDCl3) δ 165.2, 159.9, 159.2, 134.5, 130.2, 128.3, 125.9, 94.3,
59.7, 14.1, 13.5; HRMS (ESI) m/z calcd for C13H15NO3Na,
256.1052; found, 256.1055.
(Scheme 3). Several features of the one-pot method are
noteworthy. It was found that a 5-10 min microwave pulse
at 80 °C prior to increasing the temperature to 170 °C was
necessary in order to form pyrroles. This method proved to be
very expedient and high yielding for R-methyl-R-aromatic
ketoximes. For example, subjection of acetophenone oxime
(1b) and 8 to the optimized conditions gives NH-pyrrole 10b in
good yield regardless of the nucleophilic catalyst that was
employed. DABCO was used in all subsequent reactions due
to its ease of purification from the reaction mixture and low
catalyst loading. The doubly activated alkyne 12 gave higher
yields of the corresponding pyrroles 13a-g under the reaction
conditions. Importantly, tetrasubstituted pyrroles 13a and 13g
were synthesized in good yields from the respective oximes.
For increased yields and ease of purification, as the polymer-
ization of NH-pyrroles is well-documented,19 it was sometimes
necessary to add di-tert-butyl dicarbonate directly to the crude
reaction mixture to afford N-Boc-pyrroles. Unfortunately,
oxime substitution other than methyl (1h, 1i), which lacked
an aromatic group and were acyclic (1j) or aldoximes (1k), did
not afford the desired pyrroles in significant yields. We believe
that this is a result of the instability of the compounds to the
high reaction temperatures necessary for a thermal rearrange-
ment, leading to degradation/polymerization.7
Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (10b). A solution of
ethyl 3-(1-phenylethylideneaminooxy)acrylate (9b, 100 mg, 0.49
mmol) in dry toluene (2.5 mL) was heated to 170 °C for 45 min
under microwave irradiation. The solution was concentrated
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (3:1 petroleum/EtOAc) to
afford ethyl 5-phenyl-1H-pyrrole-3-carboxylate (10b, 72 mg,
84%) as an orange oil: IR (CHCl3) ν (cm-1) 3699, 3631, 2992,
2943, 2888, 2838, 1708, 1626, 1486, 1392, 1217, 1073, 891, 838,
1
640 cm-1; H NMR (400 MHz, CDCl3) δ 8.65-8.89 (m, 1H),
7.50-7.52 (m, 1H), 7.47-7.50 (m, 2H), 7.36-7.43 (m, 2H),
7.23-7.30 (m, 1H), 6.93-6.92 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H),
1.37 (t, J = 7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 164.9,
133.0, 131.7, 129.0, 127.0, 124.1, 118.1, 106.7, 59.9, 14.5; HRMS
(ESI) m/z calcd for C13H13NO2Na, 238.0844; found, 238.0845.
General Procedure A: Synthesis of NH-Pyrroles. To a stirred
solution of catalyst (0.10 equiv) and oxime (1.0 equiv) at -10 °C
in dry toluene was added dropwise an alkyne (1.0 equiv) over
15 min. The reaction mixture was allowed to warm to rt and was
subjected to a two-stage microwave irradiation sequence (stage
1, 80 °C, 5-10 min; stage 2, 170 °C, 45 min). The mixture
was concentrated under reduced pressure, and the residue was
purified by flash column chromatography on silica gel to afford
the NH-pyrrole.
In summary, we have developed a concise, robust, and
flexible nucleophilic catalysis/microwave irradiation method
for the formation of vinyl oximes and pyrroles from oximes
and electron-deficient alkynes. In particular, we note the
amenability of this method to the regioselective generation of
2,4-disubstituted and 2,3,5-trisubstituted pyrroles. Impor-
tantly, this method provides a functional group handle at C3/
Dimethyl 5-(4-bromophenyl)-1H-pyrrole-2,3-dicarboxylate
(13d). Pyrrole 13d was synthesized according to general proce-
dure A. To DABCO (10 mg, 0.09 mmol) and (E)-1-(4-bro-
mophenyl)ethanone oxime (1d, 200 mg, 0.9 mmol) in dry
toluene (2.5 mL) was added dimethylacetylenedicarboxylate
(12, 0.15 mL, 0.9 mmol), and the resultant mixture was subjected
to the two-stage microwave irradiation sequence (stage 1, 80 °C,
5 min; stage 2, 170 °C, 45 min). After workup, the residue was
purified by flash column chromatography on silica gel (7:1
petroleum/EtOAc) to afford dimethyl 5-(4-bromophenyl)-1H-
pyrrole-2,3-dicarboxylate (13d, 197 mg, 67%) as an orange
(19) Thompson, A.; Butler, R. J.; Grundy, M. N.; Laltoo, A. B. E.;
Robertson, K. N.; Cameron, T. S J. Org. Chem. 2005, 70, 3753–3756.
J. Org. Chem. Vol. 75, No. 18, 2010 6273

Ngwerume and Camp
JOCNote
oil: IR (CHCl3) ν (cm-1) 3689, 3634, 3423, 3087, 2887, 2087,
mmol), and the resultant mixture was subjected to the two-stage
microwave irradiation sequence (stage 1, 80 °C, 10 min; stage 2,
170 °C, 45 min). Di-tert-butyl dicarbonate (645 mg, 2.96 mmol),
DMAP (18 mg, 0.15 mmol), and triethylamine (0.15 mL, 1.48
mmol) were added. After workup, the residue was purified by
flash column chromatography on silica gel (12:1 petroleum/
EtOAc) to afford 1-tert-butyl 2,3-dimethyl 5-phenyl-1H-pyr-
role-1,2,3-tricarboxylate (13b, 367 mg, 70%) as an orange oil: IR
(CHCl3) ν (cm-1) 3694, 3631, 3482, 3008, 2912, 2838, 2019,
1721, 1653, 1565, 1489, 1398, 1180, 998, 899, 634 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 9.75-9.97 (br s, 1H), 7.54 (d, J =
8.1 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 6.91 (s, 1H), 3.92 (s, 3H),
3.89 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 164.1, 160.6,
133.7, 132.2, 131.0, 126.3, 122.9, 122.2, 121.5, 110.9, 52.3,
51.9; HRMS (ESI) m/z calcd for C14H12BrNO4Na, 359.9847;
found, 359.9849.
General Procedure B: Synthesis of N-Boc-Pyrroles. To a
stirred solution of DABCO (0.10 equiv) and oxime (1.0 equiv)
at -10 °C in dry toluene was added dropwise an alkyne
(1.0 equiv) over 15 min. The reaction mixture was allowed to
warm to rt and was subjected to a two-stage microwave irradia-
tion sequence (stage 1, 80 °C, 5-10 min; stage 2, 170 °C, 45 min).
To the cooled crude mixture were added di-tert-butyl dicar-
bonate (2.0 equiv), DMAP (0.10 equiv), and triethylamine
(1.0 equiv), and the resultant mixture was stirred at rt for
30 min. The mixture was concentrated under reduced pressure,
and the residue was purified by flash column chromatography
on silica gel to afford the N-Boc-pyrrole.
1750, 1603, 1534, 1447, 1332, 1126, 965, 846, 641 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.35-7.40 (m, 3H), 7.33 (m, 2H),
6.52 (s, 1H), 3.98 (s, 3H), 3.84 (s, 3H), 1.30 (s, 9H); 13C NMR
(400 MHz, CDCl3) δ 163.3, 162.9, 147.8, 135.7, 132.5, 129.7,
129.2, 128.2, 127.9, 117.4, 112.5, 86.2, 53.1, 51.9, 27.2; HRMS
(ESI) m/z calcd for C19H21NO6Na, 382.1267; found, 382.1267.
Acknowledgment. We gratefully acknowledge financial
support from the School of Chemistry at the University of
Nottingham.
1-tert-Butyl 2,3-dimethyl 5-phenyl-1H-pyrrole-1,2,3-tricar-
boxylate (13b). Pyrrole 13b was synthesized according to general
procedure B. To DABCO (17 mg, 0.15 mmol) and (E)-aceto-
phenone oxime (1b, 200 mg, 1.48 mmol) in dry toluene (2.5 mL)
was added dimethylacetylenedicarboxylate (12, 0.24 mL, 1.48
Supporting Information Available: All experimental proce-
dures, analytical data, and copies of 1H and 13C NMR spectra of
all newly synthesized products. This material is available free of
charge via the Internet at http://pubs.acs.org.
6274 J. Org. Chem. Vol. 75, No. 18, 2010