Unprecedented carbon dioxide effect on a Pd-catalysed oxidative carbonylation reaction: A new synthesis of pyrrole-2-acetic esters

Article abstract of DOI:10.1039/b203413a

It has been found that carbon dioxide effectively promotes the Pd-catalysed oxidative cyclisation-alkoxycarbonylation of (Z)-(2-en-4-ynyl)amines 1 leading to pyrrol-2-acetic esters 2.

Full text of DOI:10.1039/b203413a

Unprecedented carbon dioxide effect on a Pd-catalysed oxidative
carbonylation reaction: a new synthesis of pyrrole-2-acetic esters
Bartolo Gabriele,*a Giuseppe Salerno,*b Alessia Faziob and Fausto Bruno Campanab
a Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy.
E-mail: b.gabriele@unical.it; Fax: +39 0984 492044; Tel: +39 0984 492130
b Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy.
E-mail: g.salerno@unical.it; Fax: 39 0984 492044; Tel: +39 0984 492066
Received (in Cambridge, UK) 9th April 2002, Accepted 14th May 2002
First published as an Advance Article on the web 31st May 2002
It has been found that carbon dioxide effectively promotes
the Pd-catalysed oxidative cyclisation–alkoxycarbonylation
of (Z)-(2-en-4-ynyl)amines 1 leading to pyrrol-2-acetic esters
2.
One way for accelerating the Pd(0) reoxidation process when
inhibited by a basic substrate consists of the use of a large
excess of oxygen (which apparently favours the oxidation of HI
to iodine).3b A large excess of oxygen for the carbonylation of
enynamines, however, could not be used owing to the tendency
of the pyrrole ring to undergo oxidation reactions.5 It was
therefore necessary to solve the problem in a different manner.
A reactant able to reversibly bind the amino group [thus
‘freeing’ the HI necessary for the reoxidation of Pd(0)] without
hampering the cyclisation–alkoxycarbonylation process was
needed. We have found that carbon dioxide effectively fulfils
these requirements, through the formation of a carbamate
species. The nitrogen in the carbamate, while much less basic
than in the substrate, may still act as nucleophile, since CO2 can
be eliminated during the cyclisation process (Scheme 2).
In fact, by reacting 1a under the above-mentioned conditions
but with the addition of 50 atm of CO2, 2a was obtained in 70%
GLC yield (62% isolated) at total substrate conversion, without
any formation of 3a [eqn. (2)].†
In order to support our hypothesis regarding the effect
exerted by CO2, we synthesized allyl carbamate 4 and let it react
under the above-mentioned conditions but in the absence of
CO2. Palladium-promoted cleavage of the allyl group of 4 was
expected to afford exactly the same carbamate intermediate
formed in the CO2-assisted carbonylation of 1a (Scheme 3).‡
Indeed, by reacting 4 in the absence of CO2 and under 6 atm
of a 5+1 mixture of CO and air, after 48 h 2a was obtained in
46% GLC yield at total substrate conversion, with complete
absence of pyrrole 3a.§ In agreement with the mechanism
shown in Scheme 3, the allyl moiety of 4 was recovered as
methyl but-3-enoate.
We recently described a new synthesis of furan-2-acetic esters
by PdI2/KI-catalysed oxidative cyclisation–alkoxycarbonyla-
tion of (Z)-2-en-4-yn-1-ols.1 When we applied this method-
ology to (Z)-(2-en-4-ynyl)amines 1, however, the desired
pyrrole-2-acetic esters 2 were consistently obtained in low
yield, even after optimisation of the reaction conditions. For
example, carbonylation of (Z)-butyl(2-ethylnon-2-en-4-ynyl)-
amine 1a under 40 atm of a 3+1 mixture of carbon monoxide
and air in MeOH at 70 °C for 5 h (substrate/KI/PdI2 molar ratio
= 100+200+1, substrate concentration = 0.05 mmol mL21
MeOH) afforded a mixture of methyl 2-(1-butyl-4-ethyl-1H-
pyrrol-2-yl)hexanoate 2a (45% GLC yield, 40% isolated) and
1-butyl-4-ethyl-2-pentyl-1H-pyrrole 3a (deriving from a com-
petitive cycloisomerization process,2 9% GLC yield) at total
substrate conversion [eqn. (1)].
(1)
Under the optimised conditions found for 1a, other (Z)-(2-en-
4-ynyl)amines 1 were efficiently carbonylated to selectively
afford the corresponding pyrrole-2-acetic esters 2 in good
yields. For example, methyl (1-butyl-4-ethyl-1H-pyrrol-2-yl)-
acetate 2b was obtained in 72% GLC yield (65% isolated) from
the reaction of (Z)-butyl[2-ethyl-5-(trimethylsilanyl)pent-2-en-
4-ynyl]amine 1b at total substrate conversion [eqn. (2)].†
The striking difference in the behaviour of enynols and
enynamines can be ascribed to the basicity of the latter.3 The
alkoxycarbonylation process occurs with reduction of PdI2 to
Pd(0) and formation of 2 mol of HI. Pd(0) is then reoxidised to
the catalytically active species PdI2 by I2, formed by oxidation
of HI with oxygen4 (Scheme 1; anionic iodide ligands are
omitted for simplicity). The latter process is very fast in the case
of (Z)-2-en-4-yn-1-ols or in general with non-basic substrates.
However, substrates that are basic enough to be protonated by
HI, such as enynamines, can efficiently inhibit the reoxidation
of Pd(0) and therefore hinder the overall oxidative carbonyla-
tion process. When this occurs, the substrate may undergo
undesired side-reactions such as oligomerisation and/or oxida-
tive degradation.
(2)
Scheme 1 Mechanism of the PdI2/KI-catalysed oxidative carbonylation of 1a to give 2a. Anionic iodide ligands are omitted for clarity.
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250 mL stainless steel autoclave was charged in the presence of air with PdI2
(4.0 mg, 0.011 mmol), KI (365 mg, 2.20 mmol) and 1 (1.1 mmol) dissolved
in MeOH (22 mL). The autoclave was pressurized with stirring at room
temperature with CO2 (50 atm), CO (up to 80 atm) and air (up to 90 atm of
total pressure), and then heated at 70 °C with stirring for 5 h. After cooling,
the autoclave was degassed and solvent removed by rotary evaporation.
Crude products were easily purified by column chromatography on silica
gel using hexane/AcOEt from 99+1 to 95+5 as eluent. Characterization data
for 2a (190 mg, 62% yield; pale yellow oil): IR (film): n = 2957, 1743,
1
1463 cm21; H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H),
0.94 (t, J = 7.3 Hz, 3 H), 1.16 (t, J = 7.6 Hz, 3 H), 1.23–1.41 (m, 6 H),
1.60–1.71 (m, 2 H), 1.71–1.84 (m, 1 H); 1.98–2.13 (m, 1 H), 2.41–2.50 (m,
2 H), 3.54 (dd, J = 8.8, 6.8 Hz, 1 H), 3.66 (s, 3 H), 3.65–3.90 (m, 2 H), 5.91
(d, J = 2.0 Hz, 1 H), 6.35–6.37 (m, 1 H); 13C NMR (75 MHz, CDCl3): d =
13.8, 13.9, 14.9, 20.1, 20.2, 22.6, 30.0, 32.5, 33.8, 43.3, 46.2, 51.9, 106.2,
117.4, 125.2, 129.5, 173.9; MS (EI, 70 eV): m/z (%): 279 (13) [M+], 220
(100). For 2b (160 mg, 65%; pale yellow oil): IR (film) n = 2959, 1741,
1
1461 cm21; H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.3 Hz, 3 H),
1.16 (t, J = 7.5 Hz, 3 H), 1.27–1.41 (m, 2 H), 1.61–1.73 (m, 2 H), 2.41–2.50
(m, 2 H), 3.58 (s, 2 H), 3.69 (s, 3 H), 3.75 (t, J = 7.3 Hz, 2 H), 5.89 (d, J
= 2.0 Hz, 1 H), 6.40–6.42 (m, 1 H); 13C NMR (75 MHz, CDCl3): d = 13.8,
15.1, 20.09, 20.12, 32.6, 33.5, 46.4, 52.0, 108.4, 117.8, 123.9, 125.2, 171.2;
MS (EI, 70 eV): m/z (%): 223 (35) [M+], 164 (100). Elemental analyses
were satisfactory.
Scheme 2 Carbon dioxide effect on the PdI2/KI-catalysed oxidative
cyclisation–alkoxycarbonylation of 1a to methyl pyrrol-2-acetate 2a.
‡ In Scheme 3, the cleavage is shown to occur through oxidative addition to
a Pd(0) species formed by reduction of PdI2 under the reaction conditions.
However, the possibility of formation of a Pd(IV) intermediate by oxidative
addition to PdI2 cannot be ruled out.
§ The reaction was slower under 30 atm of CO and 10 atm of air probably
due to the competition between CO and the substrate for coordination to
palladium. A longer reaction time with respect to the analogous carbonyla-
tion of 1a carried out in the presence of CO2 was needed owing to the
kinetics of cleavage of the allyl moiety.
1 B. Gabriele, G. Salerno, F. De Pascali, M. Costa and G. P. Chiusoli, J.
Org. Chem., 1999, 64, 7693.
2 B. Gabriele, G. Salerno, A. Fazio and M. R. Bossio, Tetrahedron Lett.,
2001, 42, 1339.
3 We have already shown that the presence of an amino group in the
substrate has an adverse effect on catalysis in PdI2/KI-catalysed oxidative
alkoxycarbonylation reactions: (a) A. Bonardi, M. Costa, B. Gabriele, G.
Salerno and G. P. Chiusoli, Tetrahedron Lett., 1995, 36, 7495; (b) B.
Gabriele, G. Salerno, D. Brindisi, M. Costa and G. P. Chiusoli, Org. Lett.,
2000, 2, 625.
4 B. Gabriele, M. Costa, G. Salerno and G. P. Chiusoli, J. Chem. Soc.,
Perkin Trans. 1, 1994, 83.
5 R. A. Jones, in Comprehensive Heterocyclic Chemistry, Vol. 4, eds. A. R.
Katritzky, C. W. Rees, C. W. Bird and G. W. H. Cheeseman, Pergamon,
Oxford, 1984, pp. 246–254.
6 We have recently shown that it is possible to sequentially insert CO and
CO2 into propynylamines to give oxazolidinone derivatives, but in this
reaction CO2 was incorporated in the reaction product: A. Bacchi, G. P.
Chiusoli, M. Costa, B. Gabriele, C. Righi and G. Salerno, Chem.
Commun., 1997, 1209; G. P. Chiusoli, M. Costa, B. Gabriele and G.
Salerno, J. Mol. Catal. A: Chem., 1999, 143, 297.
7 For some recent examples, see: C. Dendrinousomara, G. Tsotsou, L. V.
Ekateriniadou, A. H. Kortsaris, C. P. Reptopoulou, A. Terzis, D. A.
Kyriakidis and D. P. Kessissoglou, J. Inorg. Biochem., 1998, 71, 171; M.
Lehr, J. Med. Chem., 1997, 40, 3381; M. Lehr, Eur. J. Med. Chem. Chim.
Ther., 1997, 32, 805.
8 For some recent examples, see: P. Langer, J. Wuckelt and M. Doring, J.
Org. Chem., 2000, 65, 729; C. Peschko and W. Steglich, Tetrahedron
Lett., 2000, 41, 9477; A. Ohta, D. Sawamoto, K. P. Jayasundera, H.
Kinoshita and K. Inomata, Chem. Lett., 2000, 492; T. L. Gilchrist, A.
Lemos and C. J. Ottaway, J. Chem. Soc., Perkin Trans. 1, 1997, 3005; D.
A. Lee and K. M. Smith, J. Chem. Soc., Perkin Trans. 1, 1997, 1215.
9 For some recent examples, see: R. Grigg and V. Savic, Chem. Commun.,
2000, 873; O. A Attanasi, L. De Crescentini, P. Filippone and F.
Mantellini, Synlett., 2000, 955; M. Johannsen, Chem. Commun., 1999,
2233; J. H. Byers, J. E. Campbell, F. H. Knapp and J. G. Thissel,
Tetrahedron Lett., 1999, 40, 2677; H.-J. Grumbach, B. Merla and N.
Risch, Synthesis, 1999, 1027; H. M. C. Ferraz, F. L. C. Pereira, F. S.
Leite, M. R. S. Marta and M. E. Payret-Arrua, Tetrahedron, 1999, 55,
10915.
Scheme 3 Cleavage and carbonylation of 4 leading to 2a.
This result should be compared with that obtained in the same
reaction carried out in the absence of CO2, which led to a
mixture of 2b and 1-butyl-4-ethyl-2-methyl-1H-pyrrole 3b in
36% and 4% GLC yield, respectively [eqn. (1)]. As we already
observed in the oxidative carbonylation of (Z)-(5-trimethylsila-
nyl)-2-en-4-yn-1-ols,1 the trimethylsilanyl group was lost in the
course of the process, thus allowing the synthesis of a-
unsubstituted pyrrolacetates starting directly from (Z)-(5-trime-
thylsilanyl-2-en-4-ynyl)amines.
The reaction reported here represents the first example in
which carbon dioxide is shown to act as a promoter in an
oxidative carbonylation process.6 From a synthetic point of
view, this is the first example of direct synthesis of pyrrole-
2-acetic esters by carbonylation of acyclic precursors. Pyrrole-
2-acetic derivatives are a very interesting class of compounds,
which are known to posses a marked pharmacological activity.7
Moreover, they have also found application as synthetic
intermediates in a variety of useful transformations.8 The
present methodology offers a convenient alternative to the so far
known methodologies9 for the synthesis of these molecules,
starting from readily available2 starting materials.
This work was supported by the Ministero dell’Università e
della Ricerca Scientifica e Tecnologica (Progetto d’Interesse
Nazionale PIN MM03027791_005).
Notes and references
† Starting (Z)-(2-en-4-ynyl)amines 1 were prepared as described in
reference 2. Representative experimental procedure for the synthesis of 2: a
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